Heterocyclic compounds, preparation methods and uses thereof

ABSTRACT

Provided herein are novel compounds, for example, compounds having a Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of preparing the compounds and methods of using the compounds, for example, in inhibiting KRAS G12C in a cell, and/or in treating various cancer such as pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to International Application Nos.PCT/CN2019/123,223, filed on Dec. 5, 2019, PCT/CN2019/087772, filed onMay 21, 2019, and PCT/CN2019/095947, filed on Jul. 15, 2019, the contentof each of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

In various embodiments, the present invention generally relates to novelheterocyclic compounds, compositions of the same, methods of preparingand methods of using the same, e.g., for inhibiting RAS and/or fortreating a number of diseases or disorders, such as pancreatic,colorectal, and lung cancers.

Background

RAS proteins regulate key cellular pathway transmitting signal receivedfrom cellular membrane receptor to downstream molecules such as Raf,MEK, ERK and PI3K, which are crucial for cell proliferation andsurvival. RAS cycles between the inactive GDP-bound form and activeGTP-bound form. RAS proteins have three gene isoforms: KRAS, NRAS andHRAS and share extensive homology (>90%) in the N-terminal domain (aminoacid 1-165). RAS is frequently mutated cancers with KRAS accounted for˜80% of all RAS mutations. KRAS mutation occurs in approximately 60% ofpancreatic cancer, 40% of colorectal cancer, 30% of lung cancer and 20%of endometrial carcinoma (F. McCormick, 2017, Clin Cancer Res 21:1797-1801). The RAS hot-spot mutations occur at codons 12, 13 and 61,with 75% of KRAS mutations occurs at codon 12 (Glycine) (D. K. Simanshu,D. V. Nissley and F. McCormick, 2017, Cell, 170: 17-33).

There is a medical need for therapeutic treatments of cancer patientswith RAS mutation such as KRAS G12C mutation.

BRIEF SUMMARY OF THE INVENTION

In various embodiments, the present disclosure provides novel compounds,pharmaceutical compositions, methods of preparing and using the same.Typically, the compounds herein are RAS inhibitors, such as KRAS G12Cinhibitors. The compounds and compositions herein are useful fortreating various diseases or disorders, such as cancer associated withKRAS G12C mutation.

In various embodiments, the present disclosure provides a compound ofFormula I or Formula II, or a pharmaceutically acceptable salt thereof:

wherein the variables are defined herein. In some embodiments, thecompound of Formula I can have a subformula of Formula I-1, I-2, I-3A,I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1,I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8, as defined herein. Insome embodiments, the present disclosure provides a compound selectedfrom compound Nos. 1-186, or a pharmaceutically acceptable salt thereof.In some embodiments, when applicable, the compound can exist as amixture of atropisomers in any ratio. In some embodiments, whenapplicable, the compound can exist as an isolated individual atropisomersubstantially free (e.g., with less than 20%, less than 10%, less than5%, less than 1%, by weight, by HPLC area, or both, or with anon-detectable amount) of the other atropisomer(s).

Certain embodiments are directed to a pharmaceutical compositioncomprising one or more of the compounds of the present disclosure (e.g.,a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C,I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1,I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, anyof compound Nos. 1-186, or a pharmaceutically acceptable salt thereof)and optionally a pharmaceutically acceptable excipient. Thepharmaceutical composition described herein can be formulated fordifferent routes of administration, such as oral administration,parenteral administration, or inhalation etc.

Certain embodiments are directed to a method of treating a disease ordisorder associated with RAS, e.g., KRAS G12C. In some embodiments, themethod comprises administering to a subject in need thereof atherapeutically effective amount of a compound of the present disclosure(e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1,I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1,I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, FormulaIV, any of compound Nos. 1-186, or a pharmaceutically acceptable saltthereof) or a therapeutically effective amount of a pharmaceuticalcomposition described herein. In some embodiments, a method of treatingcancer is provided. In some embodiments, the method comprisesadministering to a subject in need thereof a therapeutically effectiveamount of a compound of the present disclosure or a therapeuticallyeffective amount of a pharmaceutical composition described herein. Invarious embodiments, the cancer can be pancreatic cancer, endometrialcancer, colorectal cancer or lung cancer (e.g., non-small cell lungcancer). In some embodiments, the cancer is a hematological cancer(e.g., described herein). In some embodiments, the cancer is MYHassociated polyposis. In some embodiments, the cancer can be gallbladder cancer, thyroid cancer, or bile duct cancer. The administeringis not limited to any particular route of administration. For example,in some embodiments, the administering can be orally, nasally,transdermally, pulmonary, inhalationally, buccally, sublingually,intraperintoneally, subcutaneously, intramuscularly, intravenously,rectally, intrapleurally, intrathecally and parenterally. The compoundsof the present disclosure can be used as a monotherapy or in acombination therapy. In some embodiments, the combination therapyincludes treating the subject with a chemotherapeutic agent, therapeuticantibody, radiation, cell therapy, or immunotherapy.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention herein.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 is a graph showing the tumor volume growth profile vs. days onstudy in a colorectal adenocarcinoma SW837 xenograft model, followingtreatments with vehicle, AMG510 (60 mg/kg), Compound No. 44 (60 mg/kg),or Compound No. 126 (30 mg/kg).

FIG. 2 is a graph showing the tumor volume growth profile vs. days onstudy in a NSCLC H358 xenograft model, following treatments withvehicle, AMG510 (30 mg/kg), Compound No. 44 (30 mg/kg), or Compound No.126 (30 mg/kg).

FIG. 3 is a graph showing the tumor volume growth profile vs. days onstudy in a NSCLC H2122 xenograft model, following treatments withvehicle, AMG510 (60 mg/kg), or Compound No. 126 (60 mg/kg).

FIG. 4 is a graph showing the tumor volume growth profile vs. days onstudy in a NSCLC H358 xenograft model, following treatments withvehicle, carboplatin (30 mg/kg), Compound No. 145 (5 mg/kg), orcarboplatin (30 mg/kg) and Compound No. 145 (5 mg/kg).

FIG. 5 is a graph showing the tumor volume growth profile vs. days onstudy in a NSCLC H358 xenograft model, following treatments withvehicle, cisplatin (2 mg/kg), RMC-4550 (10 mg/kg), Compound No. 126 (5mg/kg), cisplatin (2 mg/kg) and Compound No. 126 (5 mg/kg), or RMC-4550(10 mg/kg) and Compound No. 126 (5 mg/kg).

FIG. 6 is a graph showing the tumor volume growth profile vs. days onstudy in a colorectal adenocarcinoma SW837 xenograft model, followingtreatments with vehicle, trametinib (1 mg/kg), Compound No. 44 (30mg/kg), or trametinib (1 mg/kg) and Compound No. 44 (30 mg/kg).

DETAILED DESCRIPTION OF THE INVENTION

In various embodiments, provided herein are novel compounds,pharmaceutical compositions, methods of preparation and methods of use.

Compounds

Some embodiments of the present disclosure are directed to novelcompounds. The compounds herein typically can be an inhibitor of a KRASprotein, particularly, a KRAS G12C mutant protein.

In some embodiments, the present disclosure provides a compound ofFormula I, or a pharmaceutically acceptable salt thereof:

wherein:X is O, NR¹⁰, S, SO₂, or an optionally substituted heterocyclic ring(e.g., 4 to 7 membered heterocyclic ring);R¹ is hydrogen, optionally substituted alkyl (e.g., C₁₋₄ alkyl), or-L-R²⁰,wherein L is absent or an optionally substituted alkylene (e.g., C₁₋₄alkylene), optionally substituted heteroalkylene (e.g., C₁₋₄heteroalkylene), optionally substituted carbocyclic ring (e.g., C₃₋₆carbocyclic ring), or optionally substituted heterocyclic ring (e.g., 4to 7 membered heterocyclic ring),wherein R²⁰ is hydrogen, optionally substituted alkyl, alkenyl, oralkynyl, e.g., optionally substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, —NR²¹R²², —OR²³, an optionally substituted heterocyclyl (e.g.,4 to 7 membered heterocyclyl),or X—R¹ represents —COOH, —COOR²³, —CONR²¹R²², —CN, optionallysubstituted alkyl, alkenyl, alkynyl, or carbocyclic ring (e.g.,cycloalkyl), for example, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, orC₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, orC₃₋₆ cycloalkyl is optionally substituted, e.g., with 1-3 groups eachindependently selected from F, OH, protected OH, and C₁₋₄ alkoxy;wherein each of R¹⁰, R²¹ and R²² at each occurrence is independentlyhydrogen, an optionally substituted alkyl, alkenyl, or alkynyl, e.g.,optionally substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl,optionally substituted heteroalkyl (e.g., C₁₋₄ heteroalkyl), optionallysubstituted carbocyclic ring (e.g., C₃₋₆ carbocyclic ring), optionallysubstituted heterocyclic ring (e.g., 4 to 7 membered heterocyclic ring),or a nitrogen protecting group; R²³ at each occurrence is independentlyhydrogen, an optionally substituted alkyl, alkenyl, or alkynyl, e.g.,optionally substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl,optionally substituted heteroalkyl (e.g., C₁₋₄ heteroalkyl), optionallysubstituted carbocyclic ring (e.g., C₃₋₆ carbocyclic ring), optionallysubstituted heterocyclic ring (e.g., 4 to 7 membered heterocyclic ring),or an oxygen protecting group;each of A¹, A², A³, A⁴, and A⁵ is independently CR³⁰ or N,wherein R³⁰ at each occurrence is independently hydrogen, halogen (e.g.,F, Cl), optionally substituted C₁₋₄ alkyl, or optionally substitutedalkoxy (e.g., C₁₋₄ alkoxy);or R¹, X, and A¹ can join together to form an optionally substitutedring structure, for example, an optionally substituted heterocyclic orheteroaryl ring;R² and R³ are each independently hydrogen, halogen, —OH, —CN, optionallysubstituted alkyl, alkenyl, or alkynyl, e.g., optionally substitutedC₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, optionally substitutedcarbocyclic ring (e.g., C₃₋₆ carbocyclic ring), optionally substitutedheterocyclic ring (e.g., 4 to 7 membered heterocyclic ring), oroptionally substituted alkoxy (e.g., C₁₋₄ alkoxy);

(hereinafter simplified as “Het”) is a heterocyclic ring (e.g., a 4-10membered heterocyclic ring), which is optionally substituted, forexample, with independently selected R⁴ group(s), (R⁴)_(n), wherein n is0, 1, 2, or 3, and R⁴ at each occurrence is independently optionallysubstituted alkyl, alkenyl, or alkynyl or a 3 or 4 membered ring, e.g.,R⁴ at each occurrence can be C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3or 4 membered ring (e.g., cyclopropyl), fluorine substituted C₁₋₄ alkyl,hydroxyl substituted C₁₋₄ alkyl, or cyano substituted C₁₋₄ alkyl; or twoR⁴ groups can join together to form a ring structure, e.g., a 3-6membered ring structure;U represents an electrophilic moiety capable of forming a covalent bondwith a cysteine residue of a KRAS protein, e.g., a KRAS G12C mutantprotein;R⁷ is hydrogen, halogen, —CN, a 3-4 membered ring, (e.g., cyclopropyl),optionally substituted alkyl, alkenyl, alkynyl, or alkoxy, for example,optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, or optionally substituted C₁₋₄alkoxyl; andR⁸ is an optionally substituted aryl or optionally substitutedheteroaryl.

In some embodiments, X in Formula I can be or include a heteroatom. Forexample, in some embodiments, X can be O. In some embodiments, X can beNR¹⁰. In some embodiments, X can also be S or SO₂. In some embodiments,X can also be a heterocyclic ring, such as an optionally substituted 4-7membered heterocyclic ring. In some embodiments, the 4-7 memberedheterocyclic ring has 1 or 2 heteroatoms, such as 1 or 2 nitrogen atoms.Various heterocyclic rings are suitable. Non-limiting suitable examplesinclude:

wherein each of which can be optionally substituted, for example, with1-3 substituents each independently selected from halogen, —OH, oxo,C₁₋₄ alkyl, and C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl or C₁₋₄ alkoxy isoptionally substituted with 1-3 fluorine, wherein the heterocyclic ringscan be attached to the remainder of Formula I via any two availablepositions. For example, when X in Formula I is an optionally substitutedpiperazine, the piperazine ring can be attached to the remainder ofFormula I via the two nitrogen atoms, two carbon atoms, a single carbonatom, or one nitrogen atom and one carbon atom, e.g.:

(optional substituent(s) not shown). Other heterocyclic rings should beunderstood similarly.

Different R¹ groups can be attached to X in Formula I. In someembodiments, R¹ can be hydrogen. In some embodiments, R¹ can beoptionally substituted C₁₋₄ alkyl, for example, methyl, ethyl,isopropyl, CHF₂, CF₃, etc.

In some embodiments, R¹ can be -L-R²⁰. In some embodiments, L can beabsent. In some embodiments, L can be a linker, for example, anoptionally substituted C₁₋₄ alkylene, optionally substituted C₁₋₄heteroalkylene, optionally substituted C₃₋₆ carbocyclic ring, oroptionally substituted 4 to 7 membered heterocyclic ring. In someembodiments, L can be a C₁₋₄ alkylene, such as —CH₂—, —CH₂—CH₂—,—CH(CH₃)—CH₂—, etc. In some embodiments, L can be an optionallysubstituted C₁₋₄ alkylene, such as with 1 or 2 substituents eachindependently F, OH, or methyl. As used herein, optionally substitutedC₁₋₄ alkylene also includes a C₁₋₄ alkylene wherein two substituents,including two gem substituents, form a cyclic structure, such as

In some embodiments, L can also be a C₁₋₄ heteroalkylene, for example,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—O—, —CH₂—CH₂—N(H)—CH₂—CH₂—,—CH₂—CH₂—O—, etc. Typically, when L is a C₁₋₄ heteroalkylene, theheteroalkylene has one or two heteroatoms, such as one oxygen, onenitrogen, or two oxygen atoms, etc. Generally, —X-L-R²⁰ does not containtwo consecutive heteroatoms. In some embodiments, L can be an optionallysubstituted C₁₋₄ heteroalkylene, such as with 1 or 2 substituents eachindependently F, —OH, or methyl. Similarly, as used herein, optionallysubstituted C₁₋₄ heteroalkylene also includes a C₁₋₄ heteroalkylene,wherein two substituents, including two gem substituents, form a cyclicstructure, such as

In some embodiments, L can also be an optionally substituted C₃₋₆carbocyclic ring. For example, in some embodiments, L can becyclopropylene, cyclobutylene, cyclopentylene, etc. Heterocyclic ringsare also suitable in some embodiments. For example, L can be a 4-7membered heterocyclic ring having one or two heteroatoms independentlyselected from O, N, and S, wherein any two available positions of theheterocyclic ring can be used to link X with R²⁰. Non-limiting suitableheterocyclic rings include those described herein, such as azetidinyl,tetrahydrofuranyl, pyrrolidinyl, piperazinyl, morpholinyl, etc. Theheterocyclic ring can be optionally substituted, for example, with 1-3substituents each independently selected from halogen, —OH, oxo, C₁₋₄alkyl, and C₁₋₄ alkoxy, wherein the C₁₋₄ alkyl or C₁₋₄ alkoxy isoptionally substituted with 1-3 fluorine.

R²⁰ typically can be hydrogen, optionally substituted C₁₋₄ alkyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, —NR²¹R²², —OR²³, or an optionally substituted 4 to 7 memberedheterocyclyl. For example, in some embodiments, R²⁰ can be hydrogen. Insome embodiments, R²⁰ can be a C₁₋₄ alkyl, such as methyl, ethyl,isopropyl, etc. In some embodiments, R²⁰ can be a C₁₋₄ alkyl substitutedwith 1-3 substituents each independently selected from F, —OH, —NH₂,—NH(C₁₋₄ alkyl) such as —NHMe, and —N(C₁₋₄ alkyl)(C₁₋₄ alkyl) such as—NMe₂ or —N(Me)(Et). For example, in some embodiments, R²⁰ can be—CH₂—OH, —CH₂—NMe₂, etc. In some embodiments, R²⁰ can be —OR²³. Forexample, in some embodiments, R²⁰ can be —OH or —O—C₁₋₄ alkyl etc. Insome embodiments, R²⁰ can be a protected OH, such as —O—C(O)—C₁₋₄ alkyl,or a silyl protected hydroxyl, such as —O-TMS. Compounds with suchprotected OH as R²⁰ can in some embodiments be used during a synthesisto provide compounds with R²⁰ being OH. In some embodiments, R²⁰ can be—NR²¹R²². For example, in some embodiments, R²⁰ can be —NH₂, —NH(C₁₋₄alkyl) such as —NHMe, or —N(C₁₋₄ alkyl)(C₁₋₄ alkyl) such as —NMe₂ or—N(Me)(Et). In some embodiments, one or both R²¹ and R²² can be anitrogen protecting group. When both R²¹ and R²² are nitrogen protectinggroups, it also includes situations where R²¹ and R²² are joined to forma ring structure, such as

Compounds with such protected NH(R) or NH₂ as R²⁰ can in someembodiments be used during a synthesis to provide compounds with R²⁰being NH(R) or NH₂. In some embodiments, R²⁰ can also be a 4-7 memberedheterocyclyl, typically having one or two heteroatoms independentlyselected from O, N, and S. Non-limiting suitable heterocyclyl includethose described herein, such as azetidinyl, tetrahydrofuranyl,pyrrolidinyl, piperazinyl, morpholinyl, etc. The heterocyclyl can beoptionally substituted, for example, with 1-3 substituents eachindependently selected from halogen, —OH, oxo, C₁₋₄ alkyl, and C₁₋₄alkoxy, wherein the C₁₋₄ alkyl or C₁₋₄ alkoxy is optionally substitutedwith 1-3 fluorine.

In some embodiments, X, R¹, and A¹ in Formula I can join together toform an optionally substituted ring structure, typically an optionallysubstituted heterocyclic or heteroaryl ring. For example, X, R¹, and A¹can together form a 4, 5, or 6 membered heterocyclic ring structure or a5 or 6-membered heteroaryl ring structure. Those skilled in the artunderstand that when X, R¹, and A¹ together form a ring structure, afused bicyclic ring is formed in Formula I, with

A¹ being shared. Non-limiting suitable ring structures include thefollowing, for illustration purposes, the fused ring structure isshowing instead of just the ring structure formed from X, R¹, and A¹ inFormula I, and optional substituents are also not shown:

In some embodiments, A² is CH. In some embodiments, A² is N.

In some embodiments, —X—R¹ in Formula I can represent a carbon linkedmoiety, where X is not a heteroatom. For example, in some embodiments,—X—R¹ in Formula I can be —COOH, —COOR²³, —CONR²¹R²², —CN, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₆ cycloalkyl is optionallysubstituted, e.g., with 1-3 groups each independently selected from F,—OH, protected OH, and C₁₋₄ alkoxy. In some embodiments, —X—R¹ inFormula I can be a hydroxyl substituted C₁₋₆ alkyl, for example,—C(CH₃)₂—OH.

In some embodiments, A¹ and A² in Formula I can both be N. In someembodiments, one of A¹ and A² in Formula I can be N, and the other of A¹and A² can be CH.

R² and R³ in Formula I can be the same or different. Typically, R² andR³ can independently be hydrogen, C₁₋₄ alkyl optionally substituted with1-3 fluorine, C₃₋₆ cycloalkyl, or halogen. For example, in someembodiments, R² and R³ can be independently selected from hydrogen,methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl. In somespecific embodiments, both R² and R³ are isopropyl. In some embodiments,both R² and R³ are cyclopropyl. In some embodiments, R² and R³ are thesame. In some embodiments, R² and R³ are different. In some embodiments,one of R² and R³ is hydrogen or methyl.

Various heterocyclic rings are suitable as Het in Formula I. It shouldbe clarified, although drawn in the formulae herein as

Het is not to be interpreted as only encompassing a 6-member monocyclicheterocyclic ring. Typically, Het can be a 4-9 membered heterocyclicring, which can be monocyclic or polycyclic (e.g., bicyclic, fused orspiro bicyclic). Het generally includes one or two ring heteroatoms,such as one or two ring nitrogen atoms. Non-limiting examples ofsuitable heterocyclic rings include the following:

wherein the point of attachments can be any of the available positions.Generally, as applicable, the two ring nitrogen atoms are attached tothe 6,6-bicyclic structure in Formula I and the electrophilic moiety U.For example, in some embodiments, Het is piperazine, which can beattached to the remainder of Formula I through the two nitrogen atoms:

(optionally substituent(s) not shown).

The compounds herein include an electrophilic moiety, U, which can reactwith a cysteine residue of a KRAS protein to form a covalent bond. Insome embodiments, U can be an electrophilic moiety containing a Michaelacceptor. For example, in some embodiments, U can be an α,β-unsaturatedcarbonyl moiety, such as

wherein R⁵ and R⁶ are defined herein. In some embodiments, U isconnected with an nitrogen atom of the Het, for example, having astructural moiety of:

wherein R⁵ and R⁶ are defined herein. In some embodiments, U can be anelectrophilic moiety, such as

wherein R⁵ and R⁶ are defined herein. In some specific embodiments, Ucan be

wherein R⁵ and R⁶ are defined herein. In some embodiments, U can be

wherein R⁵ and R⁶ are defined herein.

Various R⁵ and R⁶ are suitable. For example, in some embodiments, R⁵ andR⁶ can each be independently hydrogen, halogen, —CN, —COOR^(23A),—CONR^(21A)R^(22A), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₆ carbocyclic ring, optionally substitutedphenyl, optionally substituted 5 or 6 membered heteroaryl, or optionallysubstituted 4 to 7 membered heterocyclic ring, or R⁵ and R⁶ can jointogether to form an optionally substituted C₃₋₆ carbocyclic ring, oroptionally substituted 4 to 7 membered heterocyclic ring, wherein eachof R^(21A) and R^(22A) at each occurrence is independently hydrogen, anoptionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionallysubstituted 4 to 7 membered heterocyclic ring, or a nitrogen protectinggroup; and R^(23A) at each occurrence is independently hydrogen, anoptionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionallysubstituted 4 to 7 membered heterocyclic ring, or an oxygen protectinggroup.

In some specific embodiments, R⁵ can be hydrogen. In some embodiments,R⁵ can be a halogen, such as F or Cl. In some embodiments, R⁵ can be—CN. In some embodiments, R⁶ can be hydrogen. In some embodiments, R⁶can be a C₁₋₄ alkyl optionally substituted with 1-3 substituents eachindependently selected from F, —OH, —NH₂, —NH(C₁₋₄ alkyl) such as —NHMe,—N(C₁₋₄ alkyl)(C₁₋₄ alkyl) such as —NMe₂ or —N(Me)(Et), an optionallysubstituted 4-7 membered heterocyclyl with 1 or 2 ring heteroatomindependently selected from O, N, and S. For example, in someembodiments, R⁶ can be —CH₂—OMe, —(CH₂)_(n)—OH, —(CH₂)_(n)—NMe₂,

etc, wherein n is an integer of 1-4. In some embodiments, R⁶ can be ahalogen, such as F or Cl. In some embodiments, R⁶ can be —CN. In someembodiments, R⁶ can be —COOR^(23A), for example, —COO(C₁₋₄ alkyl). Insome embodiments, R⁶ can be —CONR^(21A)R^(22A), for example, —CON(C₁₋₄alkyl)(C₁₋₄ alkyl), —CONH(C₁₋₄ alkyl), or —CONH₂. In some embodiments,R⁶ can be an optionally substituted phenyl or 5 or 6 memberedheteroaryl, e.g.,

In some specific embodiments, both R⁵ and R⁶ are hydrogen. In somespecific embodiments, R⁵ is F or OMe, and R⁶ is hydrogen. In somespecific embodiments, R⁵ is hydrogen, and R⁶ is —CH₂—OMe or

As shown in Formula I, the Het is substituted with an electrophilicmoiety U, and can be optionally further substituted with independentlyselected R⁴ groups, (R⁴)_(n), wherein n typically is 0, 1, 2, or 3. Insome embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2.

Typically, when present, R⁴ at each occurrence can be independently C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g.,cyclopropyl), fluorine substituted C₁₋₄ alkyl, hydroxyl substituted C₁₋₄alkyl, or cyano substituted C₁₋₄ alkyl; or two R⁴ groups can jointogether to form a 3-6 membered ring structure. For example, in someembodiments, R⁴ at each occurrence can be methyl, ethyl, —CF₃, —CF₂H,—CH₂OH, or —CH₂CN. In some embodiments, n can be 1, and R⁴ can bemethyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN. In some embodiments, ncan be 2, and one R⁴ can be methyl, and the other R⁴ can be methyl,ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN.

In some embodiments, Het in Formula I, together with (R⁴)_(n) and U, isrepresented by:

wherein R⁵ and R⁶ are defined herein, for example, both R⁵ and R⁶ can behydrogen.

A³ in Formula I typically is N. Although in some embodiments, A³ canalso be CR³⁰. For example, in some embodiments, A³ can be CH.

A⁴ in Formula I typically is CH. Although in some embodiments, A⁴ canalso be N.

A⁵ in Formula I typically is N. Although in some embodiments, A⁵ canalso be CR³⁰. For example, in some embodiments, A⁵ can be CH.

In some embodiments, R⁷ in Formula I can be hydrogen, halogen, —CN, a3-4 membered ring, (e.g., cyclopropyl), optionally substituted C₁₋₄alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, or optionally substituted C₁₋₄ alkoxyl. For example, in someembodiments, R⁷ can be hydrogen, F, Cl, methyl, —CN, or —CF₃. In someembodiments, R⁷ can be F. In some embodiments, R⁷ can be Cl.

R⁸ in Formula I is typically an optionally substituted phenyl ornaphthyl or an optionally substituted 5-10 membered heteroaryl. In someembodiments, R⁸ can be a phenyl optionally substituted with 1-3 groupseach independently selected from F, Cl, —OH, —NH₂, protected hydroxylgroup, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3or 4 membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy, fluorinesubstituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy. In someembodiments, R⁸ can be a phenyl substituted with F, and optionallyfurther substituted with —OH, —NH₂, protected hydroxyl group, orprotected amino group. In some embodiments, the substituent(s) of thephenyl group can be ortho to the 6,6-bicyclic structure in Formula I.

In some embodiments, R⁸ can be a bicyclic heteroaryl (e.g., indazolyl)optionally substituted with 1-3 groups each independently selected fromF, Cl, —OH, NH₂, protected hydroxyl group, protected amino group, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g.,cyclopropyl), C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorinesubstituted C₁₋₄ alkoxy.

In some specific embodiments, R⁸ can be

In some embodiments, the present disclosure provides exemplary compoundsof Formula I having a Formula I-1 or I-2, or a pharmaceuticallyacceptable salt thereof:

wherein:

X is O, S, N, or NR¹⁰,

each of J¹ and J² is independently selected from O, S, N, CR⁴⁰, andNR⁴¹,wherein each of R⁴⁰ and R⁴¹ at each occurrence is independentlyhydrogen, —OH, —CN, halogen, an optionally substituted C₁₋₄ alkyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, an optionally substituted C₁₋₄ alkoxy, optionally substitutedC₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, oroptionally substituted 4 to 7 membered heterocyclic ring,wherein the dotted line indicates that the respective connection is asingle or double bond, provided that the bicyclic ring as a whole isaromatic, wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, Het, n, A³, A⁴, and A⁵ canbe any of those defined herein for the respective variable.In some embodiments, each of R⁴⁰ and R⁴¹ at each occurrence isindependently hydrogen or a C₁₋₄ alkyl such as methyl.

In some specific embodiments, the present disclosure also providesexemplary compounds of Formula I having a Formula I-3A, I-3B, I-3C,I-4A, I-4B, or I-4C, or a pharmaceutically acceptable salt thereof:

wherein:

A² is CH or N,

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R⁴⁰, R⁴¹, Het, n, A³, A⁴, andA⁵ can be any of those defined herein for the respective variable. Insome embodiments, each of R¹⁰, R⁴⁰ and R⁴¹ at each occurrence isindependently hydrogen or a C₁₋₄ alkyl (e.g., methyl). In someembodiments, A² is CH. In some embodiments, A² is N. In someembodiments, A³ is N, A⁴ is CH, and A⁵ is N.

In some specific embodiments, the present disclosure also providesexemplary compounds of Formula I having a Formula I-5 or I-6, or apharmaceutically acceptable salt thereof:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, L, R²⁰, Het, n, A³, A⁴, and A⁵ canbe any of those defined herein for the respective variable. In someembodiments, L is absent, an optionally substituted C₁₋₄ alkylene, oroptionally substituted 4 to 7 membered heterocyclic ring containing 1 or2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms). In someembodiments, R²⁰ is hydrogen, optionally substituted C₁₋₄ alkyl,—NR²¹R²², —OR²³, an optionally substituted 4 to 7 membered heterocyclylcontaining 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms),wherein R²¹, R²² and R²³ can be any of those defined herein for therespective variable. In some embodiments, each of R²¹, R²² and R²³ ateach occurrence is independently hydrogen or an optionally substitutedC₁₋₄ alkyl. In some embodiments, the —O-L-R²⁰ residue in Formula I-5 orI-6 can be:

In some specific embodiments, the present disclosure also providesexemplary compounds of Formula I having a Formula I-7 or I-8, or apharmaceutically acceptable salt thereof:

wherein:ring B is a 4-7 membered heterocyclic ring containing 1 or 2 ringheteroatoms, such as 1 or 2 ring nitrogen atoms, optionally substitutedwith R⁴² group(s), (R⁴²)_(m), wherein R⁴² at each occurrence isindependently hydrogen, optionally substituted C₁₋₄ alkyl, optionallysubstituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, —NR²¹R²²,or —OR²³, and m is 0, 1, or 2; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, L, R¹⁰,R²⁰, R²¹, R²², R²³, Het, n, A¹, A², A³, A⁴, and A⁵ can be any of thosedefined herein for the respective variable. In some embodiments, L isabsent, an optionally substituted C₁₋₄ alkylene, or optionallysubstituted 4 to 7 membered heterocyclic ring containing 1 or 2 ringheteroatoms (e.g., 1 or 2 ring nitrogen atoms). In some embodiments, R²⁰is hydrogen, optionally substituted C₁₋₄ alkyl, —NR²¹R²², —OR²³, anoptionally substituted 4 to 7 membered heterocyclyl containing 1 or 2ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), wherein R²¹, R²²and R²³ can be any of those defined herein for the respective variable.In some embodiments, each of R¹⁰, R²¹ and R²², as applicable, at eachoccurrence is independently hydrogen, an optionally substituted C₁₋₄alkyl, or a nitrogen protecting group. In some embodiments, R²³, asapplicable, at each occurrence is hydrogen or an optionally substitutedC₁₋₄ alkyl. In some embodiments, the

moiety in Formula I-7 is selected from —NH₂, —NHCH₃, —NHC(O)CH₃,—N(CH₃)SO₂CH₃, —N(CH₃)₂, and

In some embodiments, in Formula I-8, the ring B together with theoptional substituent(s) R⁴² is

As described above, the variables in the subformulae of Formula I, e.g.,Formula I-1, I-2, I-3A, I-3B, I-3C, I-4A, I-4B, I-4C, I-5, I-6, I-7, orI-8, can have any of the applicable respective definition defined forFormula I. For example, in some embodiments, R² and R³ in Formula I andany of its subformulae can be independently selected from hydrogen, C₁₋₄alkyl optionally substituted with 1-3 fluorine, C₃₋₆ cycloalkyl, andhalogen. In some embodiments, R² and R³ in Formula I and any of itssubformulae can be independently selected from hydrogen, methyl, ethyl,isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some embodiments, R²and R³ in Formula I and any of its subformulae can be both isopropyl orboth cyclopropyl. In some embodiments, R² and R³ in Formula I and any ofits subformulae can be different, wherein one of R² and R³ is hydrogenor methyl. In some embodiments, in Formula I and any of its subformulae,Het, together with (R⁴)_(n) and U, can be represented by

wherein n is 0, 1, or 2, wherein when n is 1 or 2, R⁴ at each occurrenceis independently methyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN. In someembodiments, in Formula I and any of its subformulae, Het, together with(R⁴)_(n) and U, can be represented by

In some embodiments, in Formula I and any of its subformulae, Het,together with (R⁴)_(n) and U, can be represented by

In some embodiments, both R⁵ and R⁶ can be hydrogen. In some specificembodiments, R⁵ is F or OMe, and R⁶ is hydrogen. In some specificembodiments, R⁵ is hydrogen, and R⁶ is —CH₂—OMe or

In some embodiments, A¹ and A² in Formula I and any of its subformulaeas applicable can be N. In some embodiments, A¹ and A² in Formula I andany of its subformulae as applicable can be different, for example, oneof A¹ and A² is N and the other of A¹ and A² is CH. In some embodiments,A³ in Formula I and any of its subformulae can be N. In someembodiments, A⁴ in Formula I and any of its subformulae can be CH. Insome embodiments, A⁵ in Formula I and any of its subformulae can be N.In some embodiments, R⁷ in Formula I and any of its subformulae can behydrogen, F, Cl, methyl, or —CF₃. In some embodiments, R⁷ can be F. Insome embodiments, R can be Cl. In some embodiments, R⁸ in Formula I andany of its subformulae can be a phenyl optionally substituted with 1-3groups each independently selected from F, Cl, —OH, NH₂, protectedhydroxyl group, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy, fluorinesubstituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy. In someembodiments, R⁸ in Formula I and any of its subformulae can be abicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3groups each independently selected from F, Cl, —OH, —NH₂, protectedhydroxyl group, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy, fluorinesubstituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy. In someembodiments, R⁸ in Formula I and any of its subformulae can be selectedfrom:

To further illustrate, using a subformula Formula I-3A as an example,some specific embodiments of the present disclosure include exemplarycompounds of Formula I having a Formula I-3A-C or Formula I-3A-N, or apharmaceutically acceptable salt thereof:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R⁴⁰, Het, and n can be any ofthose defined herein for the respective variable. For example,typically, R² and R³ in Formula I-3A-C or Formula I-3A-N can beindependently selected from hydrogen, C₁₋₄ alkyl optionally substitutedwith 1-3 fluorine, C₃₋₆ cycloalkyl, and halogen. In some embodiments, R²and R³ in Formula I-3A-C or Formula I-3A-N can be independently selectedfrom hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, andCl. In some embodiments, R² and R³ in Formula I-3A-C or Formula I-3A-Ncan be both isopropyl or both cyclopropyl. In some embodiments, R² andR³ in Formula I-3A-C or Formula I-3A-N can be different, for example,one of R² and R³ is hydrogen, F or methyl, whereas the other of R² andR³ is isopropyl or cyclopropyl. In some embodiments, in Formula I-3A-Cor Formula I-3A-N, one of R² and R³ can be F, whereas the other of R²and R³ is isopropyl or cyclopropyl, e.g., R² is F and R³ is isopropyl orcyclopropyl; or R³ is F and R² is isopropyl or cyclopropyl. In someembodiments, in Formula I-3A-C or Formula I-3A-N, one of R² and R³ canbe methyl, whereas the other of R² and R³ is isopropyl or cyclopropyl,e.g., R² is methyl and R³ is isopropyl or cyclopropyl; or R³ is methyland R² is isopropyl or cyclopropyl. As understood by those skilled inthe art, when R² and R³ are different, the compounds of Formula I-3A-Cor Formula I-3A-N can exist as a mixture of atropisomers, e.g., in anyratio. In some embodiments, when applicable, the compounds of FormulaI-3A-C or Formula I-3A-N can exist as an isolated individual atropisomersubstantially free (e.g., with less than 20%, less than 10%, less than5%, less than 1%, by weight, by HPLC area, or both, or with anon-detectable amount) of the other atropisomer. Exemplary methods forisolating atropisomers are described herein, see for example, theExamples section.

Typically, R¹⁰ and R⁴⁰ in Formula I-3A-C or Formula I-3A-N can beindependently selected from hydrogen and C₁₋₄ alkyl. In someembodiments, R⁴⁰ in Formula I-3A-C or Formula I-3A-N can be hydrogen. Insome embodiments, R¹⁰ in Formula I-3A-C or Formula I-3A-N can be a C₁₋₄alkyl, preferably, methyl.

Typically, in Formula I-3A-C or Formula I-3A-N, Het, together with(R⁴)_(n) and

can be represented by

wherein n is 0, 1, or 2, wherein when n is 1 or 2, R⁴ at each occurrenceis independently methyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN. In someembodiments, in Formula I-3A-C or Formula I-3A-N, Het, together with(R⁴)_(n) and

can be represented by

In some embodiments, in Formula I-3A-C or Formula I-3A-N, Het, togetherwith (R⁴)_(n) and

can be represented by

In some embodiments, both R⁵ and R⁶ can be hydrogen. In some specificembodiments, R⁵ is F or OMe, and R⁶ is hydrogen. In some specificembodiments, R⁵ is hydrogen, and R⁶ is —CH₂—OMe or

In some preferred embodiments, in Formula I-3A-C or Formula I-3A-N, Het,together with (R⁴)_(n) and

can be represented by

R⁷ in Formula I-3A-C or Formula I-3A-N can typically be hydrogen, F, Cl,methyl, or —CF₃. In some embodiments, R⁷ can be F. In some embodiments,R⁷ can be Cl.

R⁸ in Formula I-3A-C or Formula I-3A-N can typically be a phenyloptionally substituted with 1-3 groups each independently selected fromF, Cl, —OH, NH₂, protected hydroxyl group, protected amino group, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g.,cyclopropyl), C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorinesubstituted C₁₋₄ alkoxy. In some embodiments, R in Formula I-3A-C orFormula I-3A-N can be a bicyclic heteroaryl (e.g., indazolyl) optionallysubstituted with 1-3 groups each independently selected from F, Cl, —OH,—NH₂, protected hydroxyl group, protected amino group, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C₁₋₄alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄alkoxy. In some embodiments, R⁸ in Formula I-3A-C or Formula I-3A-N canbe selected from:

In some embodiments, R⁸ in Formula I (such as any of the subformulae,Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B,I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8) is

Some embodiments of the present disclosure are also directed to acompound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:G¹ is hydrogen, —COOH, —COOR²³, —CONR²¹R²², —CN, optionally substitutedalkyl, alkenyl, alkynyl, or carbocyclic ring (e.g., cycloalkyl), e.g.,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₆ cycloalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₆ cycloalkyl is optionallysubstituted with 1-3 groups each independently selected from F, OH,protected OH, and C₁₋₄ alkoxy; or G¹ is —X—R¹;wherein X is O, NR¹⁰, S, SO₂, or an optionally substituted 4 to 7membered heterocyclic ring; R¹ is hydrogen, optionally substituted alkyl(e.g., C₁₋₄ alkyl), or -L-R²⁰,wherein L is absent or an optionally substituted alkylene (e.g., C₁₋₄alkylene), optionally substituted heteroalkylene (e.g., C₁₋₄heteroalkylene), optionally substituted carbocyclic ring (e.g., C₃₋₆carbocyclic ring), or optionally substituted heterocyclic ring (e.g., 4to 7 membered heterocyclic ring),wherein R²⁰ is hydrogen, optionally substituted alkyl, alkenyl, oralkynyl, e.g., optionally substituted C₁₋₄ alkyl, optionally substitutedC₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, —NR²¹R²², —OR²³, anoptionally substituted 4 to 7 membered heterocyclyl,wherein each of R¹⁰, R²¹ and R²² at each occurrence is independentlyhydrogen, an optionally substituted alkyl, alkenyl, or alkynyl, e.g.,optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionallysubstituted 4 to 7 membered heterocyclic ring, or a nitrogen protectinggroup; R²³ at each occurrence is independently hydrogen, an optionallysubstituted alkyl, alkenyl, or alkynyl, e.g., optionally substitutedC₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substitutedC₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionallysubstituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7membered heterocyclic ring, or an oxygen protecting group;each of A¹, A², A³, A⁴, and A⁵ is independently CR³⁰ or N,wherein R³⁰ at each occurrence is independently hydrogen, halogen (e.g.,F, Cl), optionally substituted C₁₋₄ alkyl, optionally substituted alkoxy(e.g., C₁₋₄ alkoxy);or when applicable, R¹, X, and A¹ together form an optionallysubstituted ring structure, for example, an optionally substitutedheterocyclic or heteroaryl ring;Het is a 4-10 membered heterocyclic ring, optionally substituted with R⁴group(s), (R⁴)_(n), wherein R⁴ at each occurrence is independentlyoptionally substituted alkyl, alkenyl, or alkynyl, or a 3 or 4 memberedring, e.g., R⁴ at each occurrence can be C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), fluorine substitutedC₁₋₄ alkyl, hydroxyl substituted C₁₋₄ alkyl, or cyano substituted C₁₋₄alkyl; or two R⁴ groups can join together to form a ring structure,e.g., a 3-6 membered ring structure;U represents an electrophilic moiety capable of forming a covalent bondwith a cysteine residue of a KRAS protein, e.g., a KRAS G12C mutantprotein;R⁷ is hydrogen, halogen, —CN, a 3-4 membered ring, (e.g., cyclopropyl),optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, or optionally substituted C₁₋₄alkoxyl; andR⁸ is an optionally substituted aryl or optionally substitutedheteroaryl.

Various groups can be suitable for G¹ in Formula II. In someembodiments, G¹ can be hydrogen. In some embodiments, G¹ can be —COOH,—COOR²³, —CONR²¹R²², —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, orC₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, orC₃₋₆ cycloalkyl is optionally substituted, e.g., with 1-3 groups eachindependently selected from F, —OH, protected OH, and C₁₋₄ alkoxy. Insome embodiments, G¹ in Formula II can be a hydroxyl substituted C₁₋₆alkyl, for example, a hydroxyl substituted C₁₋₄ alkyl, such as—C(CH₃)₂—OH. In some embodiments, G¹ in Formula II can be a hydroxylsubstituted C₃₋₆ cycloalkyl, for example, a hydroxyl substituted C₃₋₅cycloalkyl. In some embodiments, G¹ in Formula II can also be —X—R¹,which can have any of the definitions defined in the context of FormulaI and its subformulae. In some embodiments, G¹ in Formula II can behydrogen, methyl, —COOH, OCF₂H, —OCF₃, cyclopropyl, —C(CH₃)₂OH, CF₃, orCN. In some preferred embodiments, G¹ in Formula II is hydrogen.

In some embodiments, the variables in Formula II, R⁴, R⁷, R⁸, Het, n, U,A¹, A², A³, A⁴, and A⁵ can be any of those defined herein in the contextof Formula I and its subformulae. For example, in some embodiments, U inFormula II can represent

wherein R⁵ and R⁶ are defined herein. For example, in some embodiments,R⁵ and R⁶ are each independently hydrogen, halogen, —CN, —COOR^(23A),—CONR^(21A)R^(22A), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₆ carbocyclic ring, optionally substitutedphenyl, optionally substituted 5 or 6 membered heteroaryl, or optionallysubstituted 4 to 7 membered heterocyclic ring, or R⁵ and R⁶ can jointogether to form an optionally substituted C₃₋₆ carbocyclic ring, oroptionally substituted 4 to 7 membered heterocyclic ring, wherein eachof R^(21A) and R^(22A) at each occurrence is independently hydrogen, anoptionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionallysubstituted 4 to 7 membered heterocyclic ring, or a nitrogen protectinggroup; and R^(23A) at each occurrence is independently hydrogen, anoptionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionallysubstituted 4 to 7 membered heterocyclic ring, or an oxygen protectinggroup. In some embodiments, in Formula II, Het, together with (R⁴)_(n)and U, can be represented by

wherein n is 0, 1, or 2, wherein when n is 1 or 2, R⁴ at each occurrenceis independently methyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN. In someembodiments, in Formula II, Het, together with (R⁴)_(n) and U, can berepresented by

In some embodiments, in Formula II, Het, together with (R⁴)_(n) and U,can be represented by

In some embodiments, both R⁵ and R⁶ can be hydrogen. In some specificembodiments, R⁵ is F or OMe, and R⁶ is hydrogen. In some specificembodiments, R⁵ is hydrogen, and R⁶ is —CH₂—OMe or

In some embodiments, A¹ and A² in Formula II can be N. In someembodiments, A¹ and A² in Formula II as applicable can be different, forexample, one of A¹ and A² is N and the other of A¹ and A² is CH. In someembodiments, A³ in Formula II can be N. In some embodiments, A⁴ inFormula II can be CH. In some embodiments, A⁵ in Formula II can be N. Insome embodiments, R⁷ in Formula II can be hydrogen, F, Cl, methyl, orCF₃. In some preferred embodiments, R⁷ is F or Cl. In some embodiments,R⁷ can be F. In some embodiments, R⁷ can be Cl. In some embodiments, R⁸in Formula II can be a phenyl optionally substituted with 1-3 groupseach independently selected from F, Cl, —OH, —NH₂, protected hydroxylgroup, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3or 4 membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy, fluorinesubstituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy. In someembodiments, R⁸ in Formula II can be a bicyclic heteroaryl (e.g.,indazolyl) optionally substituted with 1-3 groups each independentlyselected from F, Cl, —OH, —NH₂, protected hydroxyl group, protectedamino group, C₁₋₄ alkyl, C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl,and fluorine substituted C₁₋₄ alkoxy. In some embodiments, R⁸ in FormulaII can be selected from:

In some preferred embodiments, R⁸ in Formula II is

The introduction of dicyclopropyl groups in Formula II provides variousadvantages. As shown in the Examples section and FIGS. 1-3, certaincompounds of Formula II, such as Compounds 44 and 126, have betteranticancer efficacies in several animal models over the current clinicalcompound AMG-510. Introducing the 4,6-dicyclopropylpyrimidin-5-yl groupcan also lead to improved in vitro inhibition of RAS protein (such asKRAS G12C). As discussed herein, there are data showing that changing anisopropylpyrimidin-5-yl group into a correspondingcyclopropylpyrimidin-5-yl group would lead to a 2-6 fold potency drop.However, that trend is reversed when the R⁸ group in Formula II is2-amino-6-fluoro-phenyl group. For example, Compounds 44 and 126 werefound to have a better potency in inhibiting KRAS G12C than theircorresponding isopropyl analogs. Moreover, introducing the4,6-dicyclopropylpyrimidin-5-yl group can also lead to improved in vivoprofiles such as improved efficacy in treating cancer and/or safetyprofile. As discussed herein, when compared to control compounds,Compounds 44 and 126 have a better overall pharmacokinetic (“PK”)profile, such as having a better human hepatocyte clearance profile anda better overall rat PK profile with a significantly improved oralbioavailability. These data are also expected to provide superior invivo profile such as efficacy and/or safety profile.

In some embodiments, the present disclosure also provides a compound ofFormula III, or a pharmaceutically acceptable salt thereof:

wherein G¹, R², R³, R⁴, R⁷, Het, n, U, A¹, A², A³, A⁴, and A⁵ can be anyof those defined herein for the respective variable, for example, in thecontext of Formula I and its subformulae or Formula II.

For example, in some embodiments, G¹ in Formula III can be hydrogen,methyl, cyclopropyl, —C(CH₃)₂OH, CF₃, or CN. In some embodiments, U inFormula III can represent

wherein R⁵ and R⁶ are defined herein. In some embodiments, in FormulaIII, Het, together with (R⁴)_(n) and U, can be represented by

wherein n is 0, 1, or 2, wherein when n is 1 or 2, R⁴ at each occurrenceis independently methyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN. In someembodiments, in Formula III, Het, together with (R⁴)_(n) and U, can berepresented by

In some embodiments, in Formula III, Het, together with (R⁴)_(n) and U,can be represented by

In some embodiments, both R⁵ and R⁶ can be hydrogen. In some specificembodiments, R⁵ is F or OMe, and R⁶ is hydrogen. In some specificembodiments, R⁵ is hydrogen, and R⁶ is —CH₂—OMe or

In some embodiments, R² and R³ can be independently selected fromhydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl.In some specific embodiments, both R² and R³ are isopropyl. In someembodiments, both R² and R³ are cyclopropyl. In some embodiments, R² andR³ are the same. In some embodiments, R² and R³ are different. In someembodiments, one of R² and R³ is hydrogen or methyl. In someembodiments, A₁ and A² in Formula III can be N. In some embodiments, A¹and A² in Formula III can be different, for example, one of A¹ and A² isN and the other of A¹ and A² is CH. In some embodiments, A³ in FormulaIII can be N. In some embodiments, A⁴ in Formula III can be CH. In someembodiments, A⁵ in Formula III can be N. In some embodiments, R⁷ inFormula III can be hydrogen, F, Cl, methyl, or CF₃. In some embodiments,R⁷ can be F. In some embodiments, R⁷ can be Cl.

In some embodiments, the present disclosure also provides a compound ofFormula IV, or a pharmaceutically acceptable salt thereof.

wherein G¹, R², R³, R⁷, R⁸, A¹, A², A³, A⁴, and A⁵ can be any of thosedefined herein for the respective variable, for example, in the contextof Formula I and its subformulae or Formula II.

For example, in some embodiments, G¹ in Formula IV can be hydrogen,methyl, cyclopropyl, —C(CH₃)₂OH, —CF₃, or —CN. In some embodiments, R²and R³ can be independently selected from hydrogen, methyl, ethyl,isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some specificembodiments, both R² and R³ are isopropyl. In some embodiments, both R²and R³ are cyclopropyl. In some embodiments, R² and R³ are the same. Insome embodiments, R² and R³ are different. In some embodiments, one ofR² and R³ is hydrogen or methyl. In some embodiments, A¹ and A² inFormula IV can be N. In some embodiments, A¹ and A² in Formula IV can bedifferent, for example, one of A¹ and A² is N and the other of A¹ and A²is CH. In some embodiments, A³ in Formula IV can be N. In someembodiments, A⁴ in Formula IV can be CH. In some embodiments, A⁵ inFormula IV can be N. In some embodiments, R⁷ in Formula IV can behydrogen, F, Cl, methyl, or CF₃. In some embodiments, R⁷ can be F. Insome embodiments, R⁷ can be Cl. In some embodiments, R⁸ in Formula IVcan be a phenyl optionally substituted with 1-3 groups eachindependently selected from F, Cl, —OH, NH₂, protected hydroxyl group,protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy, fluorine substitutedC₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy. In some embodiments,R⁸ in Formula IV can be a bicyclic heteroaryl (e.g., indazolyl)optionally substituted with 1-3 groups each independently selected fromF, Cl, —OH, NH₂, protected hydroxyl group, protected amino group, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g.,cyclopropyl), C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorinesubstituted C₁₋₄ alkoxy. In some embodiments, R⁸ in Formula IV can beselected from:

In some embodiments, R⁸ in Formula IV is

In some embodiments, the present disclosure also provides a compoundselected from any of Compound Nos 1-186, or a pharmaceuticallyacceptable salt thereof:

In some embodiments, the present disclosure also provides a compoundselected from any of Compound Nos 1, 6, 8, 13, 20, 26, 33, 42, 44, 65,68, 69, 70, 71, 72, 117, 124, 126, 127, 145, 146, 151, 152, 157, 158,179, and 180, or a pharmaceutically acceptable salt thereof. In any ofthe embodiments described herein, unless specified or contradictory fromcontext, the compound of the present disclosure can be Compound No. 44,126, or 145, or a pharmaceutically acceptable salt thereof.

In some embodiments, to the extent applicable, the genus of compounds inthe present disclosure also excludes any of the compounds specificallyprepared and disclosed in WO2019/213516.

Additional Exemplary Embodiments

In some embodiments, the present disclosure provides the followingadditional exemplary embodiments.

-   Embodiment 1. A compound of Formula I-3A-1, I-3B-1, I-3C-1, I-4A-1,    I-4B-1, or I-4C-1, or a pharmaceutically acceptable salt thereof:

-   -   wherein in each formula as applicable:    -   A² is CH or N;    -   R² and R³ are each independently hydrogen, halogen, —OH, —CN,        optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄        alkenyl, optionally substituted C₂₋₄ alkynyl, optionally        substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7        membered heterocyclic ring, or optionally substituted C₁₋₄        alkoxy;    -   Het is a 4-10 membered heterocyclic ring, optionally substituted        with independently selected R⁴ group(s), (R⁴)_(n), wherein n is        0, 1, 2, or 3, and R⁴ at each occurrence is independently C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g.,        cyclopropyl), fluorine substituted C₁₋₄ alkyl, hydroxyl        substituted C₁₋₄ alkyl, or cyano substituted C₁₋₄ alkyl; or two        R⁴ groups can join together to form a 3-6 membered ring        structure;    -   R⁵ and R⁶ are each independently hydrogen, halogen, —CN,        —COOR^(23A), —CONR^(21A)R^(22A), optionally substituted C₁₋₆        alkyl, optionally substituted C₂₋₆ alkenyl, optionally        substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆        carbocyclic ring, optionally substituted phenyl, optionally        substituted 5 or 6 membered heteroaryl, or optionally        substituted 4 to 7 membered heterocyclic ring, or R⁵ and R⁶ can        join together to form an optionally substituted C₃₋₆ carbocyclic        ring, or optionally substituted 4 to 7 membered heterocyclic        ring, wherein each of R^(21A) and R^(22A) at each occurrence is        independently hydrogen, an optionally substituted C₁₋₄ alkyl,        optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄        alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally        substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7        membered heterocyclic ring, or a nitrogen protecting group; and        R^(23A) at each occurrence is independently hydrogen, an        optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄        alkenyl, optionally substituted C₂₋₄ alkynyl, optionally        substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆        carbocyclic ring, optionally substituted 4 to 7 membered        heterocyclic ring, or an oxygen protecting group;    -   R⁷ is hydrogen, halogen, CN, a 3-4 membered ring, (e.g.,        cyclopropyl), optionally substituted C₁₋₄ alkyl, optionally        substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl,        or optionally substituted C₁₋₄ alkoxyl;    -   R⁸ is an optionally substituted aryl or optionally substituted        heteroaryl;    -   R¹⁰ is hydrogen, an optionally substituted C₁₋₄ alkyl,        optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄        alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally        substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7        membered heterocyclic ring, or a nitrogen protecting group; and    -   each of R⁴⁰ and R⁴¹ at each occurrence is independently        hydrogen, OH, CN, halogen, an optionally substituted C₁₋₄ alkyl,        optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄        alkynyl, an optionally substituted C₁₋₄ alkoxy, optionally        substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆        carbocyclic ring, or optionally substituted 4 to 7 membered        heterocyclic ring.

-   Embodiment 2. The compound of Embodiment 1, or a pharmaceutically    acceptable salt thereof, wherein in each formula, A² is CH.

-   Embodiment 3. The compound of Embodiment 1, or a pharmaceutically    acceptable salt thereof, wherein in each formula, A² is N.

-   Embodiment 4. The compound of any one of Embodiments 1-3, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R² and R³ are independently selected from hydrogen, C₁₋₄ alkyl    optionally substituted with 1-3 fluorine, C₃₋₆ cycloalkyl, and    halogen.

-   Embodiment 5. The compound of any one of Embodiments 1-3, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R² and R³ are independently selected from hydrogen, methyl, ethyl,    isopropyl, tert-butyl, cyclopropyl, F, and Cl.

-   Embodiment 6. The compound of any one of Embodiments 1-3, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R² and R³ are both isopropyl or both cyclopropyl.

-   Embodiment 7. The compound of any one of Embodiments 1-3, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    one of R² and R³ is hydrogen, F or methyl, and the other of R² and    R³ is isopropyl or cyclopropyl.

-   Embodiment 8. The compound of any one of Embodiments 1-3, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    one of R² and R³ is F, and the other of R² and R³ is isopropyl or    cyclopropyl, e.g., R² is F and R³ is isopropyl or cyclopropyl; or R³    is F and R² is isopropyl or cyclopropyl.

-   Embodiment 9. The compound of any one of Embodiments 1-3, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    one of R² and R³ is methyl, and the other of R² and R³ is isopropyl    or cyclopropyl, e.g., R² is methyl and R³ is isopropyl or    cyclopropyl; or R³ is methyl and R² is isopropyl or cyclopropyl.

-   Embodiment 10. The compound of any one of Embodiments 1-9, or a    pharmaceutically acceptable salt thereof wherein in each formula as    applicable, the compound exists as an isolated individual    atropisomer substantially free (e.g., with less than 20%, less than    10%, less than 5%, less than 1%, by weight, by HPLC area, or both,    or with a non-detectable amount) of the other atropisomer.

-   Embodiment 11. The compound of any one of Embodiments 1-10, or a    pharmaceutically acceptable salt thereof, wherein in each formula as    applicable, R¹⁰, R⁴⁰ and R⁴¹ are independently selected from    hydrogen and C₁₋₄ alkyl.

-   Embodiment 12. The compound of any one of Embodiments 1-11, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁴⁰ is hydrogen.

-   Embodiment 13. The compound of any one of Embodiments 1-12, or a    pharmaceutically acceptable salt thereof, wherein in each formula as    applicable, R¹⁰ is a C₁₋₄ alkyl, preferably, methyl.

-   Embodiment 14. The compound of any one of Embodiments 1-13, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    Het, together with (R⁴)_(n) and

is represented by

wherein n is 0, 1, or 2, wherein when n is 1 or 2, R⁴ at each occurrenceis independently methyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN.

-   Embodiment 15. The compound of any one of Embodiments 1-13, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    Het, together with (R⁴)_(n) and

is represented by

-   Embodiment 16. The compound of any one of Embodiments 1-13, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    Het, together with (R⁴)_(n) and

is represented by

-   Embodiment 17. The compound of any one of Embodiments 1-16, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    both of R⁵ and R⁶ are hydrogen.-   Embodiment 18. The compound of any one of Embodiments 1-16, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁵ is F or OMe, and R⁶ is hydrogen.-   Embodiment 19. The compound of any one of Embodiments 1-16, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁵ is hydrogen, and R⁶ is —CH₂—OMe or

-   Embodiment 20. The compound of any one of Embodiments 1-13, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    Het, together with (R⁴)_(n) and

is represented by

-   Embodiment 21. The compound of any one of Embodiments 1-20, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁷ is hydrogen, F, Cl, methyl, or —CF₃.-   Embodiment 22. The compound of any one of Embodiments 1-20, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁷ is F.-   Embodiment 23. The compound of any one of Embodiments 1-20, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁷ is Cl.-   Embodiment 24. The compound of any one of Embodiments 1-23, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁸ is a phenyl optionally substituted with 1-3 groups each    independently selected from F, Cl, —OH, NH₂, protected hydroxyl    group, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄    alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy,    fluorine substituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄    alkoxy. Embodiment 24. The compound of any one of Embodiments 1-23,    or a pharmaceutically acceptable salt thereof, wherein R⁸ is a    bicyclic heteroaryl (e.g., indazolyl) optionally substituted with    1-3 groups each independently selected from F, Cl, —OH, —NH₂,    protected hydroxyl group, protected amino group, C₁₋₄ alkyl, C₂₋₄    alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g., cyclopropyl),    C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorine    substituted C₁₋₄ alkoxy.-   Embodiment 25. The compound of any one of Embodiments 1-23, or a    pharmaceutically acceptable salt thereof, wherein in each formula,    R⁸ is selected from:

preferably,

-   Embodiment 26. A pharmaceutical composition comprising the compound    of any one of Embodiments 1-25, or a pharmaceutically acceptable    salt thereof, and a pharmaceutically acceptable excipient.-   Embodiment 27. A method of inhibiting KRAS G12C mutant protein in a    cell, the method comprising contacting the cell with the compound of    any one of Embodiments 1-25, or a pharmaceutically acceptable salt    thereof.-   Embodiment 28. A method of treating cancer in a subject, the method    comprising administering to the subject a therapeutically effective    amount of the compound of any one of Embodiments 1-25, or a    pharmaceutically acceptable salt thereof, or the pharmaceutical    composition of embodiment 26.-   Embodiment 29. The method of Embodiment 28, wherein the cancer is a    hematologic malignancy, lung cancer (e.g., non-small cell lung    cancer), pancreatic cancer, endometrial cancer, gall bladder cancer,    thyroid cancer, bile duct cancer, and/or colorectal cancer.-   Embodiment 30. The method of Embodiment 28 or 29, further comprising    treating the subject with an additional therapy.-   Embodiment 31. The method of Embodiment 30, wherein the additional    therapy is a chemotherapeutic agent, therapeutic antibody,    radiation, cell therapy, or immunotherapy.-   Embodiment 32. The method of any one of Embodiments 28-31, wherein    the subject has a G12C mutation of KRAS, HRAS and/or NRAS.

Method of Synthesis

The compounds of the present disclosure can be readily synthesized bythose skilled in the art in view of the present disclosure. Exemplifiedsynthesis are also shown in the Examples section.

The following synthetic process of Formula I is illustrative, which canbe applied similarly by those skilled in the art for the synthesis ofcompounds of Formula II, by replacing the starting material orintermediate with an —X—R¹ group with the corresponding startingmaterial or intermediate with a G¹ group. Compounds of Formula III or IVcan also be prepared similarly. In some embodiments, the presentdisclosure also provides synthetic methods and synthetic intermediatesfor preparing the compounds of Formula I, II, III, or IV, as representedby the schemes herein.

As shown in Scheme 1, in some embodiments, compounds of Formula I can beprepared by reacting an intermediate S-2 with a heterocyclic compoundS-1 under suitable conditions, wherein Lg¹ is a leaving group such as ahalide or a sulfonate leaving group such as triflate (CF₃SO₃—) ortosylate etc. In some embodiments, S-1 can react with S-2 with a basesuch as an amine base (e.g., diisopropylethyl amine), or an inorganicbase such as a carbonate base, in a suitable solvent. In someembodiments, R^(8A) is the same as R⁸. In some embodiments, however,R^(8A) can also be different from the R⁸, and the method of synthesiscan include converting R^(8A) into R⁸. For example, in some embodiments,R^(8A) can be a leaving group, such as a halide or a sulfonate leavinggroup, and the reaction product of S-1 and S-2 can be coupled with asuitable partner to introduce the desired R⁸ group, either through onestep or multiple steps. Typically, when applicable, the introduction ofR⁸ group can be mediated by a metal catalyzed coupling reaction, such asa palladium catalyzed coupling reaction as exemplified herein. Usefulreagents and reaction conditions for palladium catalyzed couplingreactions are generally known, see for examples WO2019/051291, WO2018/119183, and WO2018/217651. In some embodiments, the suitablepartner can be a boronic acid or ester compound such as R⁸—B(OH)₂. Insome embodiments, R^(8A) can be converted into boronic acid or ester andthen couple with R⁸-Lg², wherein Lg² is a leaving group, such as ahalide or a sulfonate leaving group. Other suitable coupling reactionssuch as Stille or Negishi coupling, are known in the art and can beadapted for the synthesis of the compounds herein in view of thisdisclosure. Example 4 shows an example of reaction of S-1 and S-2, whereA³ is N, and Lg¹ is Cl. Other compounds of Formula I can be preparedsimilarly. The variables X, R¹, R², R³, R⁴, R⁷, R⁸, Het, n, U, A¹, A²,A³, A⁴, and A⁵ in Scheme 1 can be any of those defined herein.

In some cases, introducing R⁸ and/or the U group can proceed afterincorporation of a heterocyclic ring without U group. For example, asshown in Scheme 2, a heterocycle of S-3 can react with S-2 to form anintermediate S-4. Pg¹ in S-3 is typically hydrogen or a nitrogenprotecting group such as Boc. Typically, to introduce the U group, S-4can be deprotected under suitable conditions. This deprotection step canthen generate an NH moiety which can react with a suitable U group donorto provide Formula I. Generally, such U group donor can have a formulaof U-Lg³, wherein Lg³ is OH, Cl, or other suitable leaving group,exemplary U group donor can be a molecule of

or an activated form, such as an acyl chloride,

wherein R⁵ and R⁶ can be any of those defined herein. As with Scheme 1,R^(8A) can be the same as or different from R⁸. In cases when R^(8A) isdifferent from the R⁸, and the method of synthesis also includesconverting R^(8A) into R⁸. As discussed above, R^(8A) can be a leavinggroup, such as a halide or a sulfonate leaving group, and can be coupledwith a suitable partner to introduce the desired R⁸ group, eitherthrough one step or multiple steps. When applicable, the conversion ofR^(8A) to R⁸ can occur either prior to or after the introduction of theheterocyclic ring of S-3 and/or the U group. The variables X, R¹, R²,R³, R⁴, R⁷, R⁸, Het, n, U, A¹, A², A³, A⁴, and A⁵ in Scheme 2 can be anyof those defined herein.

In some embodiments, the —X—R¹ group of Formula I can be derived fromother compounds of Formula I. For example, in some embodiments, —X—R¹group in some compounds of Formula I can be —SO₂Me, and such compoundscan be prepared from corresponding compounds of Formula I where the—X—R¹ group is —S-Me through an oxidation process. Compounds of FormulaI where the —X—R¹ group is —SO₂Me can also serve as starting materialfor the synthesis of other compounds of Formula I. As will be apparentto those skilled in the art, such transformation can be carried out inany of the suitable intermediates described herein. Otherderivatizations of —X—R¹ group of Formula I are also possible and can beused in some cases for the preparation of compounds of the presentdisclosure.

Intermediate compounds of S-2 can be typically prepared by methodsincluding forming the 6,6-bicyclic ring. For example, Scheme 3 shows atypical process of preparing compounds of S-2 with A³ and A⁵ being N.Thus, a compound of S-5 can couple with S-6 through a carbonyl donor,such as oxalyl chloride to form an intermediate S-7, wherein Lg⁴ is aleaving group such as a halide (e.g., Cl) or a sulfonate leaving group.S-7 can then cyclize to form a compound of S-8, typically mediated by abase. S-8 can then be converted into a compound of S-9, e.g., thoughreacting with POCl₃ or other suitable reagents. Exemplary synthesis ofvarious compounds of S-5 are shown in the Examples section. Othercompounds of S-5 can be synthesized similarly in light of thisdisclosure. Compounds of S-6 can sometimes be commercially available orotherwise prepared by those skilled in the art. The variables X, R¹, R²,R³, R⁷, R^(8A), A¹, A², and A⁴ in Scheme 3 can be any of those definedherein.

As will be apparent to those skilled in the art, conventional protectinggroups may be necessary to prevent certain functional groups fromundergoing undesired reactions. Suitable protecting groups for variousfunctional groups as well as suitable conditions for protecting anddeprotecting particular functional groups are well known in the art. Forexample, numerous protecting groups are described in “Protective Groupsin Organic Synthesis”, 4^(th) ed. P. G. M. Wuts; T. W. Greene, JohnWiley, 2007, and references cited therein. The reagents for thereactions described herein are generally known compounds or can beprepared by known procedures or obvious modifications thereof. Forexample, many of the reagents are available from commercial supplierssuch as Aldrich Chemical Co. (Milwaukee, Wis., USA), Sigma (St. Louis,Mo., USA). Others may be prepared by procedures, or obviousmodifications thereof, described in standard reference texts such asFieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (JohnWiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (Wiley, 7^(th) Edition), and Larock's Comprehensive OrganicTransformations (Wiley-VCH, 1999), and any of available updates as ofthis filing.

Pharmaceutical Compositions

Certain embodiments are directed to a pharmaceutical compositioncomprising one or more of the compounds of the present disclosure.

The pharmaceutical composition can optionally contain a pharmaceuticallyacceptable excipient. In some embodiments, the pharmaceuticalcomposition comprises a compound of the present disclosure (e.g., acompound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C,I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1,I-4C-1, I-5, I- 6, I-7, or I-8), Formula II, Formula III, Formula IV,any of compound Nos. 1-186, or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable excipient. Pharmaceuticallyacceptable excipients are known in the art. Non-limiting suitableexcipients include, for example, encapsulating materials or additivessuch as absorption accelerators, antioxidants, binders, buffers,carriers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof. See also Remington's The Science and Practice ofPharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins,Baltimore, Md., 2005; incorporated herein by reference), which disclosesvarious excipients used in formulating pharmaceutical compositions andknown techniques for the preparation thereof.

The pharmaceutical composition can include any one or more of thecompounds of the present disclosure. For example, in some embodiments,the pharmaceutical composition comprises a compound of Formula I (e.g.,Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B,I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8),Formula II, Formula III, Formula IV, any of compound Nos. 1-186, or apharmaceutically acceptable salt thereof), e.g., in a therapeuticallyeffective amount. In any of the embodiments described herein, thepharmaceutical composition can comprise a therapeutically effectiveamount of a compound selected from compound Nos. 1-186, or apharmaceutically acceptable salt thereof.

The pharmaceutical composition can also be formulated for delivery viaany of the known routes of delivery, which include but are not limitedto oral, parenteral, inhalation, etc.

In some embodiments, the pharmaceutical composition can be formulatedfor oral administration. The oral formulations can be presented indiscrete units, such as capsules, pills, cachets, lozenges, or tablets,each containing a predetermined amount of the active compound; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.Excipients for the preparation of compositions for oral administrationare known in the art. Non-limiting suitable excipients include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated forparenteral administration (such as intravenous injection or infusion,subcutaneous or intramuscular injection). The parenteral formulationscan be, for example, an aqueous solution, a suspension, or an emulsion.Excipients for the preparation of parenteral formulations are known inthe art. Non-limiting suitable excipients include, for example,1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germoil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated forinhalation. The inhalable formulations can be, for example, formulatedas a nasal spray, dry powder, or an aerosol administrable through ametered-dose inhaler. Excipients for preparing formulations forinhalation are known in the art. Non-limiting suitable excipientsinclude, for example, lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, and mixtures of thesesubstances. Sprays can additionally contain propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The pharmaceutical composition can include various amounts of thecompounds of the present disclosure, depending on various factors suchas the intended use and potency and selectivity of the compounds. Insome embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of the present disclosure(e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1,I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1,I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, FormulaIV, any of compound Nos. 1-186, or a pharmaceutically acceptable saltthereof). In some embodiments, the pharmaceutical composition comprisesa therapeutically effective amount of the compound of the presentdisclosure and a pharmaceutically acceptable excipient. As used herein,a therapeutically effective amount of a compound of the presentdisclosure is an amount effective to treat a disease or disorder asdescribed herein, which can depend on the recipient of the treatment,the disease or disorder being treated and the severity thereof, thecomposition containing the compound, the time of administration, theroute of administration, the duration of treatment, the compound potency(e.g., for inhibiting KRAS G12C), its rate of clearance and whether ornot another drug is co-administered.

For veterinary use, a compound of the present disclosure can beadministered as a suitably acceptable formulation in accordance withnormal veterinary practice. The veterinarian can readily determine thedosing regimen and route of administration that is most appropriate fora particular animal.

In some embodiments, all the necessary components for the treatment ofKRAS-related disorder using a compound of the present disclosure eitheralone or in combination with another agent or intervention traditionallyused for the treatment of such disease can be packaged into a kit.Specifically, in some embodiments, the present invention provides a kitfor use in the therapeutic intervention of the disease comprising apackaged set of medicaments that include the compound disclosed hereinas well as buffers and other components for preparing deliverable formsof said medicaments, and/or devices for delivering such medicaments,and/or any agents that are used in combination therapy with the compoundof the present disclosure, and/or instructions for the treatment of thedisease packaged with the medicaments. The instructions may be fixed inany tangible medium, such as printed paper, or a computer readablemagnetic or optical medium, or instructions to reference a remotecomputer data source such as a world wide web page accessible via theinternet.

Method of Treatment

Compounds of the present disclosure are useful as therapeutic activesubstances for the treatment and/or prophylaxis of diseases or disordersthat are associated with RAS, e.g., KRAS G12C.

In some embodiments, the present disclosure provides a method ofinhibiting RAS-mediated cell signaling comprising contacting a cell withan effective amount of one or more compounds of the present disclosure(e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1,I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1,I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, FormulaIV, any of compound Nos. 1-186, or a pharmaceutically acceptable saltthereof). Inhibition of RAS-mediated signal transduction can be assessedand demonstrated by a wide variety of ways known in the art.Non-limiting examples include a showing of (a) a decrease in GTPaseactivity of RAS; (b) a decrease in GTP binding affinity or an increasein GDP binding affinity; (c) an increase in K_(off) of GTP or a decreasein K_(off) of GDP; (d) a decrease in the levels of signalingtransduction molecules downstream in the RAS pathway, such as a decreasein pMEK, pERK, or pAKT levels; and/or (e) a decrease in binding of RAScomplex to downstream signaling molecules including but not limited toRaf. Kits and commercially available assays can be utilized fordetermining one or more of the above.

In some embodiments, the present disclosure provides a method ofinhibiting KRAS, HRAS, and/or NRAS G12C in a cell, the method comprisingcontacting the cell with an effective amount of one or more compounds ofthe present disclosure (e.g., a compound of Formula I (e.g., FormulaI-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C,I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), FormulaII, Formula III, Formula IV, any of compound Nos. 1-186, or apharmaceutically acceptable salt thereof).

In some embodiments, the present disclosure provides a method oftreating a disease or disorder, e.g., a cancer associated with G12Cmutation of KRAS, HRAS and/or NRAS, such as a cancer associated withKRAS G12C, in a subject in need thereof. In some embodiments, the methodcomprises administering to the subject a therapeutically effectiveamount of a compound of the present disclosure (e.g., a compound ofFormula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B,I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5,I-6, I-7, or I-8), Formula II, Formula III, Formula IV, any of compoundNos. 1-186, or a pharmaceutically acceptable salt thereof) or atherapeutically effective amount of a pharmaceutical compositiondescribed herein.

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering to a subject in need thereof aneffective amount of any of the compound of the present disclosure (e.g.,a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C,I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1,I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, anyof compound Nos. 1-186, or a pharmaceutically acceptable salt thereof)or a pharmaceutical composition comprising the compound of the presentdisclosure. In some embodiments, the cancer comprises a G12C mutation ofKRAS, HRAS and/or NRAS, e.g., a KRAS G12 mutation. Determining whether atumor or cancer comprises a G12C mutation of KRAS, HRAS and/or NRAS isknown in the art, for example, as described in US2018/0334454. Invarious embodiments, the cancer can be pancreatic cancer, endometrialcancer, colorectal cancer or lung cancer (e.g., non-small cell lungcancer). In some embodiments, the cancer is a hematological cancer(e.g., described herein). In some embodiments, the cancer is MYHassociated polyposis. In some embodiments, the cancer is gall bladdercancer, thyroid cancer, or bile duct cancer. Non-limiting examples ofcancer also include acute myeloid leukemia, cancer in adolescents,adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphomaand Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas,atypical teratoid, basal cell carcinoma, bile duct cancer, bladdercancer, bone cancer, brain stem glioma, brain tumor, breast cancer,bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid,embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer,childhood cancers, chordoma, cardiac tumors, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyleoproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkinlymphoma, hypopharyngeal cancer, intraocular melanoma, islet celltumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplasia syndromes, myelodysplastic/myeloproliferativeneoplasms, multiple myeloma, merkel cell carcinoma, malignantmesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma,nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC),oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovariancancer, pancreatic cancer, papillomatosis, paraganglioma, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pharyngeal cancer, pleuropulmonary blastoma, primary central nervoussystem (CNS) lymphoma, prostate cancer, rectal cancer, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer, stomach (gastric) cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicularcancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter, trophoblastictumor, unusual cancers of childhood, urethral cancer, uterine sarcoma,vaginal cancer, vulvar cancer, or viral-induced cancer.

In some embodiments the present disclosure provides a method of treatinga disease or disorder (e.g., a cancer described herein) in a subject inneed thereof, wherein the method comprises determining if the subjecthas a G12C mutation of KRAS, HRAS and/or NRAS, e.g., KRAS G12C mutation,and if the subject is determined to have the KRAS, HRAS and/or NRAS G12Cmutation, e.g., KRAS G12C mutation, then administering to the subject atherapeutically effective dose of at least one compound of the presentdisclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A,I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1,I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III,Formula IV, any of compound Nos. 1-186, or a pharmaceutically acceptablesalt thereof) or a pharmaceutical composition comprising the at leastone compound of the present disclosure.

G12C mutation of KRAS, HRAS and/or NRAS has also been identified inhematological malignancies (e.g., cancers that affect blood, bone marrowand/or lymph nodes). Accordingly, certain embodiments are directed to amethod of treating hematological malignancy in a subject in needthereof, the method typically comprises administration of a compound ofthe present disclosure (e.g., in the form of a pharmaceuticalcomposition) to the subject. Such malignancies include, but are notlimited to leukemias and lymphomas, such as Acute lymphoblastic leukemia(ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia(CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia(CML), Acute monocytic leukemia (AMoL) and/or other leukemias. In someembodiments, the hematological malignancy can also include lymphomassuch as Hodgkins lymphoma or non-Hodgkins lymphoma, plasma cellmalignancies such as multiple myeloma, mantle cell lymphoma, andWaldenstrom's macroglubunemia.

Compounds of the present disclosure can be used as a monotherapy or in acombination therapy. In some embodiments, the combination therapyincludes treating the subject with a chemotherapeutic agent, therapeuticantibody, radiation, cell therapy, or immunotherapy. In someembodiments, compounds of the present disclosure can also beco-administered with an additional pharmaceutically active compound,either concurrently or sequentially in any order, to a subject in needthereof (e.g., a subject having a cancer associated with KRAS G12Cmutation as described herein). In some embodiments, the additionalpharmaceutically active compound can be a chemotherapeutic agent, atherapeutic antibody, etc. Any of the known chemotherapeutics can beused in combination with the compounds of the present disclosure. Insome embodiments, compounds of the present disclosure can also be usedin combination with a radiation therapy, hormone therapy, cell therapy,surgery and immunotherapy, which therapies are well known to thoseskilled in the art.

Many chemotherapeutics are presently known in the art and can be used incombination with the compounds of the present disclosure. In someembodiments, the chemotherapeutic is selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide),Iressa® (gefitinib), venetoclax, and Adriamycin as well as a host ofchemotherapeutic agents. Non-limiting examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclosphosphamide(CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel and docetaxel; retinoic acid; esperamicins; capecitabine; andpharmaceutically acceptable salts, acids or derivatives of any of theabove.

Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen,(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO).

Where desired, the compounds or pharmaceutical composition of thepresent disclosure can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

The compounds of the present disclosure may also be used in combinationwith an additional pharmaceutically active compound that disrupts orinhibits RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways. In other suchcombinations, the additional pharmaceutically active compound is a PD-1and PD-L1 antagonist. The compounds or pharmaceutical compositions ofthe disclosure can also be used in combination with an amount of one ormore substances selected from EGFR inhibitors, MEK inhibitors, PI3Kinhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunetherapies, including monoclonal antibodies, immunomodulatory imides(IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40agents, GITR agonists, CAR-T cells, and BiTEs.

Exemplary anti-PD-1 or anti-PDL-1 antibodies and methods for their useare described by Goldberg et al., Blood 110(1):186-192 (2007), Thompsonet al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al.,International Application No. PCT/JP2006/309606 (publication no. WO2006/121168 A1), each of which are expressly incorporated by referenceherein, include: pembrolizumab (Keytruda®), nivolumab (Opdivo®), Yervoy™(ipilimumab) or Tremelimumab (to CTLA-4), galiximab (to B7.1), M7824 (abifunctional anti-PD-L1/TGF-β Trap fusion protein), AMP224 (to B7DC),BMS-936559 (to B7-H1), MPDL3280A (to B7-H1), MEDI-570 (to ICOS), AMG404, AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to LAG-3), BMS-663513(to CD137), PF-05082566 (to CD137), CDX-1127 (to CD27), anti-OX40(Providence Health Services), huMAbOX40L (to OX40L), Atacicept (toTACI), CP-870893 (to CD40), Lucatumumab (to CD40), Dacetuzumab (toCD40), Muromonab-CD3 (to CD3), Ipilumumab (to CTLA-4). Immune therapiesalso include genetically engineered T-cells (e.g., CAR-T cells) andbispecific antibodies (e.g., BiTEs). Non-limiting useful additionalagents also include anti-EGFR antibody and small molecule EGFRinhibitors such as cetuximab (Erbitux), panitumumab (Vectibix),zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib (Tarceva),lapatinib (TykerB), etc. Non-limiting useful additional agents alsoinclude CDK inhibitors such as CDK4/6 inhibitors, such as seliciclib,UCN-01, P1446A-05, palbociclib (PD-0332991), abemaciclib, dinaciclib,P27-00, AT-7519, RGB286638, and SCH727965, etc. Non-limiting usefuladditional agents also include MEK inhibitors such as trametinib(Mekinist®), CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119,ARRY-142886, ARRY-438162, and PD-325901. WO 2019/213516 describes a listof additional agents that can be used in combination with KRAS G12Cinhibitors. These additional agents can also be used in combination withthe compounds of the present disclosure.

As shown in the Examples section, the combination of Compound Nos. 44,126, and 145 with various agents including platinum based drugs(cisplatin or carboplatin), a SHP2 inhibitor (RMC-4550,(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol),a MEK inhibitor (trametinib), were shown to provide synergistic effectin reducing tumor volume in several animal models. Thus, in someembodiments, compounds of the present disclosure (e.g., compound 44,126, or 145) can be used in combination with a platinum based drug(e.g., cisplatin or carboplatin), a SHP2 inhibitor (such as RMC-4550,RMC-4630, TNO155), and/or a MEK inhibitor (such as trametinib).

The administering herein is not limited to any particular route ofadministration. For example, in some embodiments, the administering canbe orally, nasally, transdermally, pulmonary, inhalationally, buccally,sublingually, intraperintoneally, subcutaneously, intramuscularly,intravenously, rectally, intrapleurally, intrathecally and parenterally.In some embodiments, the administering is orally.

Dosing regimen including doses can vary and can be adjusted, which candepend on the recipient of the treatment, the disease or disorder beingtreated and the severity thereof, the composition containing thecompound, the time of administration, the route of administration, theduration of treatment, the compound potency, its rate of clearance andwhether or not another drug is co-administered.

Definitions

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof.

It is also meant to be understood that a specific embodiment of avariable moiety herein can be the same or different as another specificembodiment having the same identifier.

Suitable atoms or groups for the variables herein are independentlyselected. The definitions of the variables can be combined. UsingFormula I as an example, any of the definitions of one of X, R¹, R², R³,R⁴, R⁷, R⁸, Het, n, U, A¹, A², A³, A⁴, and A⁵ in Formula I can becombined with any of the definitions of the others of X, R¹, R², R³, R⁴,R⁷, R⁸, Het, n, U, A¹, A², A³, A⁴, and A⁵ in Formula I. Such combinationis contemplated and within the scope of the present invention.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds of the present disclosure can comprise one or more asymmetriccenters and/or axial chirality, and thus can exist in various isomericforms, e.g., enantiomers and/or diastereomers. For example, thecompounds described herein can be in the form of an individualenantiomer, diastereomer, atropisomer, or geometric isomer, or can be inthe form of a mixture of stereoisomers, including racemic mixtures andmixtures enriched in one or more stereoisomer. Isomers can be isolatedfrom mixtures by methods known to those skilled in the art, includingchiral high performance liquid chromatography (HPLC) and the formationand crystallization of chiral salts; or preferred isomers can beprepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers including racemic mixtures. When a stereochemistry isspecifically drawn, it should be understood that with respect to thatparticular chiral center or axial chirality, the compound existspredominantly as the as-drawn stereoisomer, such as with less than 20%,less than 10%, less than 5%, less than 1%, by weight, by HPLC area, orboth, or with a non-detectable amount of the other stereoisomer(s). Thepresence and/or amounts of stereoisomers can be determined by thoseskilled in the art in view of the present disclosure, including throughthe use of chiral HPLC.

Compounds of the present disclosure can have atropisomers. In any of theembodiments described herein, when applicable, the compound of thepresent disclosure can exist as a mixture of atropisomers in any ratio.In some embodiments, when applicable, the compound can exist as anisolated individual atropisomer substantially free (e.g., with less than20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC area,or both, or with a non-detectable amount) of the other atropisomer(s).The Examples section shows some exemplary isolated atropisomers ofcompounds of the present disclosure. As understood by those skilled inthe art, when the rotation is restricted around a single bond, e.g., abiaryl single bond, a compound may exist in a mixture of atropisomerswith each individual atropisomer isolable.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

As used herein, the term “compound(s) of the present disclosure” or“compound(s) of the present invention” refers to any of the compoundsdescribed herein according to Formula I (e.g., Formula I-1, I-2, I-3A,I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1,I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III,Formula IV, any of compound Nos. 1-186, isotopically labeled compound(s)thereof (such as a deuterated analog wherein one of the hydrogen atomsis substituted with a deuterium atom with an abundance above its naturalabundance), possible stereoisomers thereof (including diastereoisomers,enantiomers, and racemic mixtures), geometric isomers thereof,atropisomers thereof, tautomers thereof, conformational isomers thereof,and/or pharmaceutically acceptable salts thereof (e.g., acid additionsalt such as HCl salt or base addition salt such as Na salt). For theavoidance of doubt, Compound Nos. 1-186 or Compounds 1-186 refers to thecompounds described herein labeled as integers 1, 2, 3, . . . , 186, seefor example the title compounds of Examples 1-23 and Table 1. Hydratesand solvates of the compounds of the present disclosure are consideredcompositions of the present disclosure, wherein the compound(s) is inassociation with water or solvent, respectively.

Compounds of the present disclosure can exist in isotope-labeled or-enriched form containing one or more atoms having an atomic mass ormass number different from the atomic mass or mass number mostabundantly found in nature. Isotopes can be radioactive ornon-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon,phosphorous, sulfur, fluorine, chlorine, and iodine include, but are notlimited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I.Compounds that contain other isotopes of these and/or other atoms arewithin the scope of this invention.

As used herein, the phrase “administration” of a compound,“administering” a compound, or other variants thereof means providingthe compound or a prodrug of the compound to the individual in need oftreatment.

As used herein, the term “alkyl” as used by itself or as part of anothergroup refers to a straight- or branched-chain aliphatic saturatedhydrocarbon. In some embodiments, the alkyl which can include one totwelve carbon atoms (i.e., C₁₋₁₂ alkyl) or the number of carbon atomsdesignated (i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, aC₃ alkyl such as propyl or isopropyl, etc.). In one embodiment, thealkyl group is a straight chain C₁₋₁₀ alkyl group. In anotherembodiment, the alkyl group is a branched chain C₃₋₁₀ alkyl group. Inanother embodiment, the alkyl group is a straight chain C₁₋₆ alkylgroup. In another embodiment, the alkyl group is a branched chain C₃₋₆alkyl group. In another embodiment, the alkyl group is a straight chainC₁₋₄ alkyl group. For example, a C₁₋₄ alkyl group as used herein refersto a group selected from methyl, ethyl, propyl (n-propyl), isopropyl,butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. An optionallysubstituted C₁₋₄ alkyl group refers to the C₁₋₄ alkyl group as defined,optionally substituted with one or more permissible substituents asdescribed herein. As used herein, the term “alkylene” as used by itselfor as part of another group refers to a divalent radical derived from analkyl group. For example, non-limiting straight chain alkylene groupsinclude —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—, and the like.

As used herein, the term “heteroalkyl” refers to an alkyl group asdefined above, with one or more carbon being replaced with a heteroatom,such as O or N. A heteroalkyl can be designated by its number ofcarbons. For example, a C₁₋₄ heteroalkyl refers to a heteroalkyl groupcontaining 1-4 carbons. When optionally substituted, either theheteroatom or the carbon atom of the heteroalkyl group can besubstituted with a permissible substituent. As used herein, the term“heteroalkylene” as used by itself or as part of another group refers toa divalent radical derived from a heteroalkyl group.

As used herein, the term “alkenyl” as used by itself or as part ofanother group refers to an alkyl group as defined above containing one,two or three carbon-to-carbon double bonds. In one embodiment, thealkenyl group is a C₂₋₆ alkenyl group. In another embodiment, thealkenyl group is a C₂₋₄ alkenyl group. Non-limiting exemplary alkenylgroups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl,pentenyl, and hexenyl.

As used herein, the term “alkynyl” as used by itself or as part ofanother group refers to an alkyl group as defined above containing oneto three carbon-to-carbon triple bonds. In one embodiment, the alkynylhas one carbon-carbon triple bond. In one embodiment, the alkynyl groupis a C₂₋₆ alkynyl group. In another embodiment, the alkynyl group is aC₂₋₄ alkynyl group. Non-limiting exemplary alkynyl groups includeethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

As used herein, the term “alkoxy” as used by itself or as part ofanother group refers to a radical of the formula OR^(a1), wherein R^(a1)is an alkyl.

As used herein, the term “haloalkyl” as used by itself or as part ofanother group refers to an alkyl substituted with one or more fluorine,chlorine, bromine and/or iodine atoms. In preferred embodiments, thehaloalkyl is an alkyl group substituted with one, two, or three fluorineatoms. In one embodiment, the haloalkyl group is a C₁₋₁₀ haloalkylgroup. In one embodiment, the haloalkyl group is a C₁₋₆ haloalkyl group.In one embodiment, the haloalkyl group is a C₁₋₄ haloalkyl group.

“Carbocyclyl” or “carbocyclic” as used by itself or as part of anothergroup refers to a radical of a non-aromatic cyclic hydrocarbon grouphaving from 3 to 10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”) and zeroheteroatoms in the non-aromatic ring system. The carbocyclyl group canbe either monocyclic (“monocyclic carbocyclyl”) or contain a fused,bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) and can be saturated or can be partially unsaturated.“Carbocyclyl” also includes ring systems wherein the carbocyclic ring,as defined above, is fused with one or more aryl or heteroaryl groupswherein the point of attachment is on the carbocyclic ring, and in suchinstances, the number of carbons continue to designate the number ofcarbons in the carbocyclic ring system. Non-limiting exemplarycarbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl,cyclopentenyl, and cyclohexenyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”).

“Heterocyclyl” or “heterocyclic” as used by itself or as part of anothergroup refers to a radical of a 3- to 10-membered non-aromatic ringsystem having ring carbon atoms and 1 to 4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen, sulfur,boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or a fused, bridged, or spiro ring system, such as a bicyclic system(“bicyclic heterocyclyl”), and can be saturated or can be partiallyunsaturated. Heterocyclyl bicyclic ring systems can include one or moreheteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocyclic ring, as defined above, is fused withone or more carbocyclyl groups wherein the point of attachment is eitheron the carbocyclyl or heterocyclic ring, or ring systems wherein theheterocyclic ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclic ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclicring system.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” as used by itself or as part of another group refers to a radicalof a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in acyclic array) having 6-14 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C₆₋₁₄ aryl”). In someembodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has ten ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In someembodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”;e.g., anthracyl). “Aryl” also includes ring systems wherein the arylring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system.

“Aralkyl” as used by itself or as part of another group refers to analkyl substituted with one or more aryl groups, preferably, substitutedwith one aryl group. Examples of aralkyl include benzyl, phenethyl, etc.When an aralkyl is said to be optionally substituted, either the alkylportion or the aryl portion of the aralkyl can be optionallysubstituted.

“Heteroaryl” as used by itself or as part of another group refers to aradical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ringsystem (e.g., having 6 or 10 pi electrons shared in a cyclic array)having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). Inheteroaryl groups that contain one or more nitrogen atoms, the point ofattachment can be a carbon or nitrogen atom, as valency permits.Heteroaryl bicyclic ring systems can include one or more heteroatoms inone or both rings. “Heteroaryl” includes ring systems wherein theheteroaryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the point of attachment is on theheteroaryl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heteroaryl ringsystem. “Heteroaryl” also includes ring systems wherein the heteroarylring, as defined above, is fused with one or more aryl groups whereinthe point of attachment is either on the aryl or heteroaryl ring, and insuch instances, the number of ring members designates the number of ringmembers in the fused (aryl/heteroaryl) ring system. Bicyclic heteroarylgroups wherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” as used by itself or as part of another group refers toan alkyl substituted with one or more heteroaryl groups, preferably,substituted with one heteroaryl group. When a heteroaralkyl is said tobe optionally substituted, either the alkyl portion or the heteroarylportion of the heteroaralkyl can be optionally substituted.

As commonly understood by those skilled in the art, alkylene,alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, andheteroarylene refer to the corresponding divalent radicals of alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, respectively.

An “optionally substituted” group, such as an optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroarylgroups, refers to the respective group that is unsubstituted orsubstituted. In general, the term “substituted”, whether preceded by theterm “optionally” or not, means that at least one hydrogen present on agroup (e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent can be the same or different at each position. Typically,when substituted, the optionally substituted groups herein can besubstituted with 1-5 substituents. Substituents can be a carbon atomsubstituent, a nitrogen atom substituent, an oxygen atom substituent ora sulfur atom substituent, as applicable.

Unless expressly stated to the contrary, combinations of substituentsand/or variables are allowable only if such combinations are chemicallyallowed and result in a stable compound. A “stable” compound is acompound that can be prepared and isolated and whose structure andproperties remain or can be caused to remain essentially unchanged for aperiod of time sufficient to allow use of the compound for the purposesdescribed herein (e.g., therapeutic administration to a subject).

In some embodiments, the “optionally substituted” non-aromatic groupherein can be unsubstituted or substituted with 1, 2, or 3 substituentsindependently selected from F, Cl, —OH, oxo (as applicable), C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1 or 2 ringheteroatoms independently selected from O, S, and N, 4-7 memberedheterocyclyl containing 1 or 2 ring heteroatoms independently selectedfrom O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, isoptionally substituted with 1, 2, or 3 substituents independentlyselected from F, —OH, oxo (as applicable), C₁₋₄ alkyl,fluoro-substituted C₁₋₄ alkyl (e.g., CF₃), C₁₋₄ alkoxy andfluoro-substituted C₁₋₄ alkoxy. In some embodiments, the “optionallysubstituted” aromatic group (including aryl and heteroaryl groups)herein can be unsubstituted or substituted with 1, 2, or 3 substituentsindependently selected from F, Cl, —OH, —CN, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, phenyl, 5or 6 membered heteroaryl containing 1 or 2 ring heteroatomsindependently selected from O, S, and N, 4-7 membered heterocyclylcontaining 1 or 2 ring heteroatoms independently selected from O, S, andN, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from F,—OH, oxo (as applicable), C₁₋₄ alkyl, fluoro-substituted C₁₋₄ alkyl,C₁₋₄ alkoxy and fluoro-substituted C₁₋₄ alkoxy.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, OP(R^(cc))₃⁺X⁻, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups; wherein X is a counterion; or two geminal hydrogens on a carbonatom are replaced with the group ═O, ═S, ═NN(R^(bb))₂,═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa),═NR^(bb), or ═NOR^(cc); each instance of R^(aa) is, independently,selected from C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(aa) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(d)d groups;wherein X⁻ is a counterion;each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or twogeminal R^(dd) substituents can be joined to form ═O or ═S; wherein X isa counterion;each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; andeach instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, F⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, and a carborane anion(e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplary counterions which may bemultivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻, B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻,carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate,malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate,azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and thelike), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups attached to a nitrogen atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc), and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl,ar-C₁₋₁₀ alkyl, heteroar-C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined herein.Nitrogen protecting groups are well known in the art and include thosedescribed in detail in Protective Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated by reference herein.

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and—P(═O)(N(R^(bb))₂)₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein. In certain embodiments, the oxygen atom substituentpresent on an oxygen atom is an oxygen protecting group (also referredto as a hydroxyl protecting group). Oxygen protecting groups are wellknown in the art and include those described in detail in ProtectiveGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)edition, John Wiley & Sons, 1999, incorporated herein by reference.Exemplary oxygen protecting groups include, but are not limited to,alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl,substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM),benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., silyl etherssuch as trymethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl(TIPS), t-butyldimethylsilyl (TBDMS), etc., acetals or ketals, such astetrahydropyranyl (THP), esters such as formate, acetate, chloroacetate,dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate,etc., carbonates, sulfonates such as methanesulfonate (mesylate),benzylsulfonate, and tosylate (Ts), etc.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry, for example, it can refer to an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples ofsuitable leaving groups include, but are not limited to, halogen (suchas F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

The term “subject” (alternatively referred to herein as “patient”) asused herein, refers to an animal, preferably a mammal, most preferably ahuman, who has been the object of treatment, observation or experiment.

As used herein, the terms “treat,” “treating,” “treatment,” and the likerefer to eliminating, reducing, or ameliorating a disease or condition,and/or symptoms associated therewith. Although not precluded, treating adisease or condition does not require that the disease, condition, orsymptoms associated therewith be completely eliminated. As used herein,the terms “treat,” “treating,” “treatment,” and the like may include“prophylactic treatment,” which refers to reducing the probability ofredeveloping a disease or condition, or of a recurrence of apreviously-controlled disease or condition, in a subject who does nothave, but is at risk of or is susceptible to, redeveloping a disease orcondition or a recurrence of the disease or condition. The term “treat”and synonyms contemplate administering a therapeutically effectiveamount of a compound described herein to a subject in need of suchtreatment.

EXAMPLES

The various starting materials, intermediates, and compounds of thepreferred embodiments can be isolated and purified where appropriateusing conventional techniques such as precipitation, filtration,crystallization, evaporation, distillation, and chromatography.Characterization of these compounds can be performed using conventionalmethods such as by melting point, mass spectrum, nuclear magneticresonance, and various other spectroscopic analyses. Exemplaryembodiments of steps for performing the synthesis of products describedherein are described in greater detail infra.

Example 1. Synthesis of Compound 1

Step 1:

A mixture of 4,6-dichloropyrimidin-5-amine (8.15 g, 50 mmol),cyclopropylboronic acid (21.5 g, 250 mmol), K₃PO₄ (31.8 g, 150 mmol),Pd₂(dba)₃ (4.6 g, 5 mmol) and Sphos (4.1 g, 10 mmol) in toluene (180 mL)and water (20 mL) was stirred at 95° C. under nitrogen for 30 minutes.The reaction was cooled to room temperature and then washed with water.The mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash column chromatography on silica gel(petroleum ether to petroleum ether/ethyl acetate=4/1) to afford 1-1.

Step 2: To a suspension of 2,5,6-trichloronicotinic acid (10 g, 44 mmol)in dichloromethane (100 mL) at room temperature was added oxalylchloride (11 g, 88 mmol) and 15 drops of dry DMF. After 30 minutes, theresulting solution was concentrated to give a residue which wasdissolved in dioxane (40 mL). 100 mL of ammonia (28% NH₃ in water) wasadded dropwise at 0° C., and the reaction mixture was allowed to stirfor an additional 10 minutes, filtered, and washed with water. Thefilter cake was collected and freeze-dried to afford 1-2.

Step 3: A solution of 1-2 (550 mg, 2.44 mmol) in DCE (5 mL) was treatedwith oxalyl chloride (464.5 mg, 3.66 mmol). The mixture was stirred for45 minutes at 80° C. and then concentrated. The residue was dissolved inacetonitrile (5 mL) and cooled to −10° C., and a solution of 1-1 (1 g,5.86 mmol) in acetonitrile (5 mL) was added. The resulting solution wasstirred at room temperature overnight and then concentrated. The residuewas purified by flash column chromatography on silica gel (ethylacetate/petroleum ether=1/9 to 1/3) to afford 1-3.

Step 4: To a stirred solution of 1-3 (845 mg, 1.98 mmol) in THF (40 mL)at −20° C. was added KHMDS (5 mL, 1 M in THF, 5.0 mmol). The resultingmixture was then stirred at room temperature for 2 hours. The reactionwas quenched with sat. NH₄Cl (aq.). and extracted with ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by flash column chromatography onsilica gel (ethyl acetate/petroleum ether=1/9 to 2/1) to afford 1-4.

Step 5: A mixture of 1-4 (250 mg, 0.64 mmol), DIEA (107.6 mg, 0.83 mmol)and POCl₃ (117.9 mg, 0.77 mmol) in MeCN (3 mL) was stirred at 80° C. for30 minutes. The reaction mixture was cooled to −10° C. and DIEA (248.4mg, 1.92 mmol) was added, followed by addition of a solution oftert-butyl (3S)-3-methylpiperazine-1-carboxylate (384.9 mg, 1.92 mmol)in MeCN (1 mL) dropwise. The resulting solution was stirred at roomtemperature for 1 hour. The reaction was quenched with ice and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash column chromatography on silica gel (ethyl acetate/petroleumether=1/4 to 1/1) to afford 1-5.

Step 6: A mixture of 1-5 (100 mg, 0.18 mmol), 2-fluorophenylboronic acid(48.9 mg, 0.35 mmol), KOAc (85.7 mg, 0.87 mmol) and Pd(dppf)Cl₂ (12.8mg, 0.017 mmol) in 1,4-dioxane (2 mL) and H₂O (3 drops) was stirred at90° C. for 1.5 h under N₂. The mixture was cooled and extracted withEtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by a prep-TLC (CH₂Cl₂/MeOH=15/1)to afford 1-6.

Step 7: A solution of 1-6 (70 mg, 0.11 mmol) and HCl in 1,4-dioxane (4M, 1 mL, 4 mmol) in DCM (2 mL) was stirred at 0° C. for 2 h. The mixturewas then concentrated to give a residue which was dissolved in DCM (3mL). DIEA (171.7 mg, 1.33 mmol) was added at 0° C. followed by additionof acryloyl chloride (10.2 mg, 0.11 mmol) in DCM (1 mL) dropwise. Themixture was stirred at 0° C. for 10 minutes, and was then concentratedto give a residue which was purified by a prep-HPLC (aqueous NH₄HCO₃ (10mM) with acetonitrile (30%-54%)) to afford compound 1 (30 mg). LCMS(ESI, m/z): [M+H]⁺=586.3; HNMR (300 MHz, DMSO-d₆, ppm): δ 8.73 (s, 1H),8.47 (s, 1H), 7.55 (m, 1H), 7.40-7.28 (m, 3H), 6.87 (m, 1H), 6.24-6.18(m, 11H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 4.98 (brs, 1H), 4.43-4.03 (m,3H), 3.90-3.70 (m, 1H), 3.66-3.44 (m, 1H), 3.27-3.08 (m, 1H), 1.85-1.68(m, 2H), 1.35 (d, J=6.7 Hz, 3H), 0.97-0.81 (m, 8H). FNMR (282 MHz,DMSO-d₆, ppm): δ −113.10 (1F).

Example 2 Synthesis of Compound 42

Step 1: To a stirred solution of tert-butyl(2S,5R)-2,5-dimethylpiperazine-1-carboxylate (2.14 g, 10 mmol) andacryloyl chloride (990 mg, 11 mmol) in THF (30 mL) was added a solutionof triethylamine (3.03 g, 30 mmol) in THE (10 mL) at −10° C. under N₂atmosphere. The mixture was allowed to warm to room temperaturegradually and stirred for 0.5 hour. Then the reaction mixture wasdiluted with ethyl acetate, washed with water and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated. Theresidue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate=1/10) to afford 42-1.

Step 2: To a solution of 42-1 (804 mg, 3 mmol) in DCM (5 mL) was addedtrifluoroacetic acid (2 mL). The mixture was stirred at room temperaturefor 1.5 hours and then concentrated to afford 42-2.

Step 3: To a solution of 42-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol)in acetonitrile (20 mL) was added POCl₃ (367 mg, 2.4 mmol) dropwise atroom temperature. The mixture was stirred at 80° C. for 2 hours. Thenthe mixture was cooled to −10° C. and treated with DIEA (3.87 g, 30mmol), followed by addition of a solution of 42-2 (1.58 g, 4 mmol) inacetonitrile (10 mL). The mixture was stirred at room temperature for 1hour, then diluted with ethyl acetate, washed with water and brine. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The residue was purified by column chromatography on silica gel (DCM toDCM/MeOH=10/1) to afford 42-4.

Step 4: A mixture of 42-4 (104 mg, 0.2 mmol), (2-fluorophenyl)boronicacid (42 mg, 0.3 mmol), potassium acetate (157 mg, 1.6 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II) (15 mg,0.02 mmol) in 1,4-dioxane (3 mL) and water (3 drops) was stirred at 90°C. for 3 hours under nitrogen atmosphere. The reaction mixture wasfiltered and the filtrate was purified by a prep-HPLC (acetonitrile with0.05% TFA in water: 25% to 95%) to afford compound 42 (58 mg). LCMS(ESI, m/z): [M+H]⁺=584.1; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.73 (s, 1H),8.33-29 (m, 1H), 7.58-7.51 (m, 1H), 7.40-7.29 (m, 3H), 6.87-6.74 (m,1H), 6.17-6.13 (m, 1H), 5.74-5.69 (m, 1H), 4.91-4.72 (m, 1.5H),4.51-4.43 (m, 0.5H), 4.20-4.12 (m, 1.5H), 3.82-3.77 (m, 2H), 3.49-3.45(m, 0.5H), 1.73-1.66 (m, 2H), 1.30-1.15 (m, 6H), 0.99-0.72 (m, 8H). FNMR(376 MHz, DMSO-d₆, ppm): δ −113.32 (1F), −128.68 (1F).

Example 3 Synthesis of Compound 13

Step 1: To a 250 mL sealed tube was added 2,6-dimethylheptane-3,5-dione(10 g, 64.0 mmol), urea (7.69 g, 128.0 mmol), EtOH (120 mL) and con. HCl(50 mL) at room temperature. The resulting mixture was stirred at 100°C. for 18 hours. The mixture was cooled to room temperature andconcentrated. Water and ethyl acetate were added, and the organic layerwas separated, dried over anhydrous Na₂SO₄, filtered and concentrated toafford 13-1.

Step 2: To a stirred solution of 13-1 (8.40 g, 46.6 mmol) in con. H₂SO₄(100 mL) was added fuming HNO₃ (11.75 g, 186.4 mmol) dropwise at roomtemperature. The resulting mixture was stirred at 65° C. for 6 hours.The mixture was cooled to room temperature, diluted with water, andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated toafford 13-2.

Step 3: To a stirred solution of 13-2 (4 g, 17.8 mmol) and K₂CO₃ (4.9 g,35.5 mmol) in acetone (80 mL) was added2-bromo-N,N-dimethylethan-1-amine hydrobromide (4.96 g, 21.3 mmol) inportions at room temperature. The resulting mixture was stirred at 60°C. for 16 hours under nitrogen atmosphere, cooled to room temperature,and concentrated. The residue was diluted with water and extracted withDCM/MeOH (10/1). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to afford 13-3.

Step 4: A mixture of 13-3 (300 mg, 1.0 mmol), 10% Pd/C (38.1 mg) andMeOH (10 mL) was stirred at room temperature under H₂ atmosphere forovernight. The resulting mixture was filtered, and the filtrate wasconcentrated to afford 13-4.

Followed similar steps in example 1 to synthesize 13. LCMS (ESI, m/z):[M+H]⁺=677.4; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.48 (s, 1H), 7.60-7.44(m, 1H), 7.32 (m, 2H), 7.20 (t, J=6.7 Hz, 1H), 6.98-6.79 (m, 1H), 6.22(d, J=15.6 Hz, 1H), 5.78 (d, J=10.2 Hz, 1H), 4.98 (brs, 1H), 4.50-4.28(m, 4H), 4.21-4.03 (m, 1H), 3.90-3.60 (m, 2H), 3.30-3.20 (m, 1H),2.71-2.59 (m, 4H), 2.21 (s, 6H), 1.35 (d, J=6.6 Hz, 3H), 1.06 (d, J=6.5Hz, 6H), 0.91 (d, J=6.4 Hz, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.70(1F).

Example 4 Synthesis of Compound 8

Step 1: A mixture of 8-3 (350 mg, 0.82 mmol), (2-fluorophenyl)boronicacid (172 mg, 1.23 mmol), potassium acetate (640 mg, 6.56 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II) (58 mg,0.08 mmol) in 1,4-dioxane (7 mL) and water (0.2 mL) was stirred at 90°C. for 2 hours under nitrogen atmosphere. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by flash column chromatography onsilica gel (petroleum ether to petroleum ether/ethyl acetate=2/1) toafford 8-4.

Step 2: To a solution of 8-4 (82 mg, 0.17 mmol) and DIEA (360 mg, 2.8mmol) in acetonitrile (3 mL) was added POCl₃ (135 mg, 0.88 mmol)dropwise at room temperature. The reaction mixture was heated at 80° C.for 30 minutes, cooled to −10° C. and DIEA (129 mg, 1 mmol) was added,followed by addition of a solution of 8-1 (118 mg, 0.26 mmol) inacetonitrile (2 mL). The mixture was stirred at room temperature for 1hour, diluted with ice-water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified by a prep-HPLC (acetonitrile with 0.05% of TFAin water: 5% to 65%) to afford compound 8 (26.2 mg). LCMS (ESI, m/z):[M+H]⁺=620.1; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.44-8.42 (m, 1H),7.52-7.46 (m, 1H), 7.31-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.85-6.81 (m,1H), 6.20-6.16 (m, 1H), 5.73 (dd, J=10.4, 2.4 Hz, 1H), 4.94 (brs, 1H),4.34-4.24 (m, 2H), 4.12-3.99 (m, 1H), 3.84 (s, 3H), 3.55-3.43 (m, 2H),3.24-3.08 (m, 1H), 2.60-2.58 (m, 2H), 1.31 (d, J=6.4 Hz, 3H), 1.02 (d,J=6.8 Hz, 6H), 0.87 (d, J=6.4 Hz, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ−114.78 (1F).

Example 5 Synthesis of Compound 6

Step 1: To a solution of 13-2 (7 g, 31 mmol) in trichlorophosphate (40mL) was added DMF (0.4 g, 5.6 mmol). The mixture was stirred at 105° C.for 0.5 hour, cooled, and concentrated. The crude residue was dilutedwith ethyl acetate and ice-water. The organic layer was separated anddried over sodium sulfate, filtered and concentrated. The residue waspurified by flash column chromatography on silica gel (petroleum etherto petroleum ether/ethyl acetate=10/1) to afford 6-1.

Step 2: A mixture of 6-1 (0.95 g, 3.7 mmol) and ammonia (8 mL) intetrahydrofuran (40 mL) was stirred at room temperature for 20 hours.The reaction mixture was diluted with ethyl acetate, and washed withwater and brine. The organic layer was dried over sodium sulfate,filtered and concentrated to afford 6-2.

Step 3: A mixture of 6-2 (1.1 g, 4.9 mmol), di-tert-butyl dicarbonate(3.2 g, 14.7 mmol) and 4-dimethylaminopyridine (0.6 g, 4.9 mmol) intetrahydrofuran (30 mL) was refluxed for 0.5 hour. The reaction mixturewas diluted with ethyl acetate, and washed with water and brine. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The residue was purified by flash column chromatography on silica gel(petroleum ether to petroleum ether/ethyl acetate=10/1) to afford 6-3.

Step 4: A mixture of 6-3 (1.7 g, 4 mmol), ammonia (0.05 mL) and 10% Pd/C(400 mg) in methanol (40 mL) was stirred at room temperature underhydrogen atmosphere for 16 hours. The reaction mixture was filteredthrough Celite and the filtrate was concentrated to afford 6-4.

Step 5: To a solution of 6-6 (50 mg, 0.062 mmol) in dichloromethane (1.5mL) was added trifluoroacetic acid (0.5 mL) at room temperature. Themixture was stirred for 1 hour, concentrated, and purified by aprep-HPLC (acetonitrile with 0.05% of TFA in water: 25% to 95%) toafford compound 6 (17.8 mg). LCMS (ESI, m/z): [M+H]⁺=605.1; HNMR (400MHz, DMSO-d₆, ppm): δ 8.41-8.39 (m, 1H), 7.53-7.47 (m, 1H), 7.32-7.26(m, 2H), 7.21-7.17 (m, 1H), 6.85-6.81 (m, 1H), 6.20-6.15 (m, 1H), 5.73(dd, J=10.4, 2.4 Hz, 1H), 4.92 (brs, 1H), 4.34-4.23 (m, 2H), 4.13-3.98(m, 1H), 3.58-3.43 (m, 2H), 3.24-3.08 (m, 1H), 2.50-2.48 (m, 2H), 1.29(d, J=6.8 Hz, 3H), 0.98 (d, J=6.4 Hz, 6H), 0.83 (d, J=6.8 Hz, 6H). FNMR(376 MHz, DMSO-d₆, ppm): δ −114.67 (1F).

Example 6 Synthesis of Compound 20

Step 1: To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine(2.4 g, 12.5 mmol) in ethanol (50 mL) was added stannous chloride (8.3g, 43.7 mmol), and the reaction mixture was heated at 80° C. for 4hours. The reaction was quenched with a saturated sodium carbonatesolution and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (petroleum ether to petroleum ether/ethyl acetate=5/1) toafford 20-1.

Step 2: To a mixture of 20-1 (1.8 g, 8.6 mmol), cyclopropylboronic acid(3.7 g, 42.8 mmol), potassium phosphate (6.5 g, 30.2 mmol) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (705 mg, 1.72 mmol) intoluene (60 mL) and H₂O (20 mL) was addedtris(dibenzylideneacetone)-dipalladium (789 mg, 0.86 mmol) under N₂atmosphere. The reaction mixture was stirred at 95° C. for 3 hours,cooled to room temperature, diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified byflash column chromatography on silica gel (petroleum ether to petroleumether/ethyl acetate=5/1) to afford 20-2.

Step 3: To a solution of 20-2 (1.4 g, 6.3 mmol) in dichloromethane (70mL) was added 3-chloroperoxybenzoic acid (3.3 g, 19.0 mmol) at 0° C.,and the reaction mixture was stirred at room temperature for 2 hours.The mixture was filtered and the filtrate was concentrated. The residuewas purified by flash column chromatography on silica gel (petroleumether to petroleum ether/ethyl acetate=2/1) to afford 20-3.

Step 4: To a solution of 2-(dimethylamino)ethanol (1.5 g, 18 mmol) intetrahydrofuran (50 mL) was added sodium hydride (1.4 g, 36 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 15 minutes, and 20-3(1.4 g, 5.5 mmol) was added. After stirring for 3 hours at roomtemperature, the mixture was quenched with water and concentrated. Theresidue was purified by a prep-HPLC (acetonitrile with 0.05% of TFA inwater: 5% to 25%) to afford 20-4 as a TFA salt.

Followed similar steps in example 1 and example 4 to synthesize 20. LCMS(ESI, m/z): [M+H]⁺=673.1; HNMR (400 MHz, DMSO-d₆, ppm): δ 9.46 (brs,1H), 8.42 (s, 1H), 7.54-7.52 (m, 1H), 7.34-7.29 (m, 3H), 6.85-6.78 (m,1H), 6.17 (d, J=16.8 Hz, 1H), 5.74 (dd, J=10.8, 2.0 Hz, 1H), 4.92 (brs,1H), 4.52-4.46 (m, 2H), 4.38-3.98 (m, 3H), 3.78-3.57 (m, 2H), 3.44-3.32(m, 3H), 2.80 (d, J=4.4 Hz, 6H), 1.71-1.67 (m, 2H), 1.31 (d, J=6.8 Hz,3H), 1.08-0.80 (m, 8H). FNMR (376 MHz, DMSO-d₆, ppm): δ −113.43 (1F).

Example 7 Synthesis of Compound 33

Step 1: To a mixture of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine(2.4 g, 10 mmol), cyclopropyl-boronic acid (3.7 g, 42.8 mmol), sodiumcarbonate (3.2 g, 30.2 mmol) in toluene (60 mL) and H₂O (20 mL) wasadded Pd(PPh₃)₄ (1.1 g, 1.0 mmol) under N₂ atmosphere. The reactionmixture was stirred at 95° C. for 3 hours. Then the reaction mixture wascooled, diluted with water and extracted with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (petroleum ether to petroleum ether/ethyl acetate=6/1) toafford 33-1.

Step 2: To a solution of 33-1 (2.0 g, 8.0 mmol) in dichloromethane (80mL) was added 3-chloroperoxy-benzoic acid (3.5 g, 20.0 mmol) at 0° C.,and the reaction mixture was stirred at room temperature for 2 hours.The mixture was filtered and the filtrate was concentrated. The residuewas purified by flash column chromatography on silica gel (petroleumether to petroleum ether/ethyl acetate=4/1) to afford 33-2.

Step 3: To a solution of 33-2 (940 mg, 5.0 mmol) and DIEA (1.29 g, 10.0mmol) in tetrahydrofuran (12 mL) was added N,N-dimethylethylenediamine(510 mg, 5.8 mmol), and the mixture was stirred at room temperature for2 hours. Then the reaction solution was concentrated, and the residuewas purified by flash column chromatography on silica gel (petroleumether to petroleum ether/ethyl acetate=2/1) to afford 33-3.

Step 4: A mixture of 33-3 (700 mg, 3.6 mmol) and Zn powder (1.3 g, 20.0mmol) in ethanol (20 mL) and saturated NH₄Cl solution (3.0 mL) wasstirred at 85° C. for 4 hours. The reaction mixture was filtered and thefiltrate was concentrated. The residue was purified by flash columnchromatography on silica gel (petroleum ether to petroleum ether/ethylacetate=1/1) to afford 33-4.

Followed similar steps in example 1 and example 4 to synthesize 33. LCMS(ESI, m/z): [M+H]⁺=656.2; HNMR (400 MHz, methanol-d₄, ppm): δ 8.25-8.20(m, 1H), 7.53-7.51 (m, 1H), 7.48-7.44 (m, 1H), 7.27-7.19 (m, 2H),6.83-6.81 (m, 1H), 6.26 (dd, J=16.8, 3.2 Hz, 1H), 5.79 (dd, J=10.8, 1.6Hz, 1H), 5.10-5.00 (m, 1H), 4.49-4.43 (m, 2H), 4.20-4.04 (m, 1H),3.82-3.80 (m, 1H), 3.73-3.65 (m, 2H), 3.64-3.52 (m, 1H), 3.41-3.31 (m,3H), 2.89 (s, 6H), 1.62-1.50 (m, 2H), 1.45 (d, J=6.0 Hz, 3H), 1.05-1.01(m, 4H), 0.88-0.73 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −115.0(1F), −129.2 (1F).

Example 8 Synthesis of Compound 26

Followed similar steps in example 1 to synthesize 26-1.

Step 1: To a solution of 26-1 (500 mg, 0.75 mmol) in dichloromethane (8mL) was added 3-chloroperoxybenzoic acid (260 mg, 1.5 mmol) at 0° C.,and the reaction mixture was stirred at room temperature for 2 hours.The mixture was filtered and the filtrate was concentrated. The residuewas purified by flash column chromatography on silica gel (ethylacetate/dichloromethane=1/1 to ethyl acetate) to afford 26-2.

Step 2: To a solution of 26-2 (300 mg, 0.43 mmol) in DMSO (4 mL) wasadded NaCN (106 mg, 2.2 mmol) at 0° C., and the reaction mixture wasstirred at room temperature for 18 hours. Then the reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (petroleum ether/ethyl acetate=1/1) to afford 26-3.

Followed similar step in example 1 to synthesize 26. LCMS (ESI, m/z):[M+H]⁺=595.3; HNMR (300 MHz, DMSO-d₆, ppm): δ 8.43-8.35 (m, 1H),7.62-7.57 (m, 1H), 7.44-7.27 (m, 3H), 6.95-6.81 (m, 1H), 6.21 (d, J=17.0Hz, 1H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 4.98 (brs, 1H), 4.39-4.32 (m,2H), 4.19-4.03 (m, 1H), 3.85-3.78 (m, 1H), 3.70-3.42 (m, 1H), 3.25-3.11(m, 1H), 1.98-1.85 (m, 2H), 1.35 (d, J=6.7 Hz, 3H), 1.15-0.90 (m, 8H).FNMR (282 MHz, DMSO-d₆, ppm): δ −113.63 (1F), −128.34 (1F).

Example 9 Synthesis of Compound 71

Step 1: To a solution of 5-nitro-1,3-benzothiazole (8.0 g, 44.4 mmol) intetrahydrofuran (50 mL) was added a solution of isopropylmagnesiumbromide in tetrahydrofuran (2 M, 24.4 mL, 48.8 mmol) at 0° C. Themixture was stirred at 0° C. for 0.5 hour. Then DDQ (12.1 g, 53.2 mmol)in tetrahydrofuran (10 mL) was added thereto. The resulting mixture wasstirred at 0° C. for 1 hour and at room temperature for another 2 hours.The mixture was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate=20/1) to afford 71-1.

HNMR (300 MHz, DMSO-d₆, ppm): δ 9.62 (s, 1H), 8.27 (d, J=6.0 Hz, 1H),7.84 (d, J=9.0 Hz, 1H), 3.56-3.47 (m, 1H), 1.54 (d, J=6.9 Hz, 6H).

Step 2: A mixture of 71-1 (79 mg, 0.35 mmol), NH₄Cl (189 mg, 3.5 mmol),Zn (231 mg, 3.5 mmol) in MeOH (100 mL) and H₂O (10 mL) was stirred at55° C. for 2 hours. The resulting mixture was filtered, the filter cakewas washed with ethyl acetate. The combined organic layers wereconcentrated to give a residue which was purified by flash columnchromatography on silica gel (petroleum ether/ethyl acetate=20/1) toafford 71-2.

Followed similar steps in example 1 to synthesize 71. LCMS (ESI, m/z):[M+H]⁺=603.3; HNMR (300 MHz, DMSO-d₆, ppm): δ 9.42 (s, 1H), 8.46-8.42(m, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.52-7.42 (m, 1H), 7.32-7.12 (m, 4H),6.97-6.81 (m, 1H), 6.25-6.19 (d, J=17.4 Hz, 1H), 5.79 (dd, J=10.2, 2.4Hz, 1H), 5.05-4.85 (m, 1H), 4.45-4.00 (m, 3H), 3.90-3.40 (m, 2H),3.00-3.30 (m, 1H), 2.99-2.85 (m, 1H), 1.44-1.26 (m, 9H). FNMR (282 MHz,DMSO-d₆, ppm): δ −114.01 (1F).

Example 10 Synthesis of Compound 68

Step 1: A solution of 71-2 (2.0 g, 10.6 mmol) in HOAc (40 mL) was addedBr₂ (1.7 g, 10.6 mmol) at 0° C. The resulting mixture was stirred for 2hours at room temperature. The mixture was purified by flash columnchromatography on silica gel (petroleum ether/ethyl acetate=99/1) toafford 68-1.

Step 2: To a solution of 71-2 (2.4 g, 8.8 mmol) in 20 mL of1,4-dioxane/H₂O (5/1) was added trimethyl-1,3,5,2,4,6-trioxatriborinane(2.2 g, 17.6 mmol) and Na₂CO₃ (2.35 g, 22.1 mmol) and Pd(PPh₃)₄ (1.0 g,0.89 mmol). The resulting mixture was stirred at 100° C. for 5 hoursunder N₂ atmosphere. After cooling to room temperature, the mixture waswashed with water and then extracted with ethyl acetate. The organiclayer was washed with brine, dried over MgSO4. concentrated and purifiedby preparative TLC (petroleum ether/ethyl acetate=5/1) to afford 68.

Followed similar steps in example 1 to synthesize 68. LCMS (ESI, m/z):[M+H]⁺=617.1; HNMR (300 MHz, DMSO-d₆, ppm): δ 9.33 (s, 1H), 8.49 (s,1H), 7.95 (d, J=0.9 Hz, 1H), 7.51-7.44 (m, 1H), 7.31-7.16 (m, 3H),6.98-6.81 (m, 1H), 6.22 (d, J=16.7 Hz, 1H), 5.78 (dd, J=10.2, 2.4 Hz,1H), 4.97 (brs, 1H), 4.49-4.28 (m, 2H), 4.25-4.02 (m, 1H), 3.87-3.45 (m,2H), 3.22-3.05 (m, 1H), 3.02-2.88 (m, 1H), 2.05-1.98 (m, 1H), 1.42-1.32(m, 6H), 1.27 (dd, J=6.9, 1.8 Hz, 3H). FNMR (282 MHz, DMSO-d₆, ppm): δ−114.35 (1F).

Example 11 Synthesis of Compound 70

Step 1: To a stirred mixture of 2,6-dibromo-3-nitropyridine (50 g, 177mmol) and Na₂CO₃ (37.6 g, 355 mmol) in EtOH (500 mL) was added asolution of CH₃NH₂ in THF (107 mL, 214 mmol) dropwise at 0° C. Theresulting mixture was stirred at room temperature overnight. Theresulting mixture was filtered, the filter cake was washed with ethylacetate. The filtrate was concentrated to give a solid which wasre-crystallized from ethyl acetate/petroleum ether (10/1) to afford70-1.

Step 2: To a solution of 70-1 (10 g, 43 mmol) and XantPhos Pd G3 (408mg, 0.43 mmol) in THF (100 mL) was added a solution of isopropylzincbromide in THF (0.5 M, 33 mL, 66 mmol) dropwise at room temperature. Theresulting mixture was stirred at 30° C. for 3 hours under argonatmosphere. The reaction was quenched with sat. aqueous NH₄Cl solutionat room temperature. The resulting mixture was extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, concentrated and purified by flash columnchromatography on silica gel (petroleum ether/ethyl acetate=20/1) toafford 70-2.

Step 3: To a solution of 70-2 (1.5 g, 7.7 mmol) in DMF (15 mL) was addedNBS (1.64 g, 9.2 mmol) in DMF (15 mL) dropwise at 0° C. The resultingmixture was stirred at 0° C. for 2 hours, diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith brine and dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated to give a residue which was purified by flashcolumn chromatography on silica gel (petroleum ether/ethyl acetate=10/1)to afford 70-3.

Step 4: A mixture of 70-3 (1.5 g, 5.5 mmol), NH₄Cl (2.34 g, 43.7 mmol)and Zn (1.8 g, 27.4 mmol) in methanol (15 mL)/H₂O (8 mL) was stirred at60° C. for 2 hours. The mixture was filtered, concentrated to removemethanol and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to afford 70-4.

Step 5: A solution of 70-4 (1.2 g, 4.9 mmol) in formic acid (10 mL) wasstirred at 100° C. overnight. Then cooled, diluted with water andneutralized to pH=7 with NaOH. The resulting mixture was extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, and concentrated to afford 70-5.

Step 6: A mixture of 70-5 (2.9 g, 11.4 mmol) and Cu (362 mg, 5.7 mmol)in ammonia (40 mL) was stirred at room temperature for 0.5 hour and thenstirred at 100° C. overnight. The resulting mixture was extracted withethyl acetate, dried over anhydrous Na₂SO₄, concentrated and purified byflash column chromatography on silica gel (petroleum ether/ethylacetate=3/1) to afford 70-6.

Followed similar steps in example 1 to synthesize 70. LCMS (ESI, m/z):[M+H]⁺=601.4; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.51-8.39 (m, 2H),7.92-7.88 (m, 1H), 7.53-7.45 (m, 1H), 7.35-7.12 (m, 3H), 6.94-6.81 (m,1H), 6.23 (d, J=16.4 Hz, 1H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 5.10-4.85(m, 1H), 4.45-4.00 (m, 3H), 3.83 (s, 3H), 3.73-3.60 (m, 1H), 3.55-3.40(m, 1H), 3.15-3.05 (m, 1H), 2.85-2.75 (m, 1H), 1.35 (dd, J=13.1, 6.6 Hz,3H), 1.16 (d, J=6.7 Hz, 3H), 1.06 (dd, J=6.7, 2.3 Hz, 3H). FNMR (376MHz, DMSO-d₆, ppm): δ −114.16 (1F).

Example 12 Synthesis of Compound 65

Step 1: To a solution of 70-6 (30 mg, 1.57 mmol) in HOAc (15 mL) andCHCl₃ (6 mL) was added Br₂ (252 mg, 1.57 mmol) in HOAc (1 mL) dropwiseat 0° C. The mixture was stirred at room temperature for 0.5 hour andthen quenched with sat. NaHCO₃ solution. The resulting mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, concentrated and purified byflash column chromatography on silica gel (petroleum ether/ethylacetate=1/9) to afford 65-1.

Step 2: A mixture of 65-1 (200 mg, 0.74 mmol),trimethyl-1,3,5,2,4,6-trioxatriborinane (559 mg, 4.45 mmol), Pd(PPh₃)₄(85 mg, 0.074 mmol), Na₂CO₃ (196 mg, 1.85 mmol) and in dioxane/H₂O (5/1,2 mL) was stirred at 110° C. for 3 hours under nitrogen atmosphere. Theresidue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate=1/1) to afford 65-2.

Followed similar steps in example 1 to synthesize 65. LCMS (ESI, m/z):[M+H]⁺=615.3; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.48-8.47 (m, 1H), 8.33(s, 1H), 7.49-7.46 (m, 1H), 7.30-7.17 (m, 3H), 6.94-6.83 (m, 1H),6.24-6.19 (m, 1H), 5.79-5.76 (m, 1H), 4.97 (brs, 1H), 4.44-4.32 (m, 2H),4.19-4.04 (m, 1H), 3.90-3.46 (m, 5H), 3.16-3.10 (m, 1H), 2.78-2.76 (m,1H), 2.21-2.15 (m, 3H), 1.35 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H),1.02 (dd, J=6.4, 1.8 Hz, 3H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.52(1F).

Example 13 Synthesis of Compound 72

Step 1: To a solution of N¹-methyl-4-nitrobenzene-1,2-diamine (25 g, 149mmol) and trimethyl orthoformate (200 mL) in DMF (300 mL) was addedconc. HCl (16 mL) dropwise at room temperature. After stirring at roomtemperature overnight, the mixture was concentrated. The residue wasdissolved in ethyl acetate. The mixture was basified with Et₃N. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated to give aresidue which was purified by flash column chromatography on silica gel(dichloromethane/methanol=12/1) to afford 72-1.

Step 2: To a solution of 72-1 (32 g, 180 mmol) in tetrahydrofuran (80mL) was added i-PrMgCl.LiCl (210 mL, 1.3 M in THF, 271 mmol) at 0° C.The mixture was stirred at 0° C. for 0.5 hour. Then DDQ (49.2 g, 216mmol) in tetrahydrofuran (40 mL) was added. The mixture was stirred at0° C. for 1 hour. The reaction was quenched with water at 0° C. Theresulting mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography to afford 72-2.

Step 3: A mixture of 72-2 (7.0 (petroleum ether/ethyl acetate=4/1) g,31.9 mmol) and 10% Pd/C (3.4 g) in methanol (30 mL) was stirred at roomtemperature overnight under hydrogen atmosphere. The resulting mixturewas filtered, the filter cake was washed with MeOH. The filtrate wasconcentrated to afford 72-3.

Followed similar steps in example 1 to synthesize 72. LCMS (ESI, m/z):[M+H]⁺=600.4; HNMR (300 MHz, DMSO-d₆, ppm): δ 8.44-8.36 (m, 1H), 8.15(s, 1H), 7.48-7.43 (m, 1H), 7.41-7.38 (d, J=8.4 Hz, 1H), 7.27-7.14 (m,3H), 7.02-6.98 (dd, J=10.5, 2.1 Hz, 1H), 6.91-6.85 (m, 1H), 6.24-6.19(d, J=16.2 Hz, 1H), 5.79-5.75 (dd, J=12.9, 2.4 Hz, 1H), 4.95-4.85 (m,1H), 4.36-4.05 (m, 3H), 3.81 (s, 3H), 3.67-3.40 (m, 2H), 3.20-2.90 (m,1H), 2.75-2.70 (m, 1H), 1.39-1.29 (m, 9H). FNMR (282 MHz, DMSO-d₆, ppm):δ −114.19 (1F).

Example 14 Synthesis of Compound 69

Method A

Step 1: To a solution of 4-isopropyl-1-methyl-1,3-benzodiazol-5-amine(6.0 g, 31.7 mmol) in HOAc (20 mL) was added Br₂ (5.1 g, 31.7 mmol) inHOAc (2 mL) dropwise at 0° C. After stirring for 1 hour, the mixture wasconcentrated. The residue was partitioned between ethyl acetate and 2 MNaOH. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=4/1) to afford 69-1.

Step 2: A mixture of 69-1 (3.8 g, 14.2 mmol),trimethyl-1,3,5,2,4,6-trioxatriborinane (3.6 g, 28.4 mmol), Na₂CO₃ (3.0g, 28.4 mmol) and Pd(PPh₃)₄ (1.64 g, 1.42 mmol) in 30 mL of dioxane/H₂O(5/1) was stirred at 100° C. for 5 hours under N₂ atmosphere. Aftercooling to room temperature, water was added and the mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄ and concentrated. The residue was purifiedby a preparative TLC (petroleum ether/ethyl acetate=1/1) to afford 69-2.

Method B

Step 1: To a solution of 2-fluoro-4-methylaniline (10.0 g, 79.9 mmol) inH₂SO₄ (100 mL) was added a solution of conc. HNO₃ (5.66 g, 87.9 mmol) inH₂SO₄ (11.2 mL) dropwise at 0° C. After stirring for 3 hours at 0° C.,the reaction mixture was poured into ice water (600 mL) and theresulting mixture was basified by slow addition of an NaOH solution (180g dissolved in 240 mL water). Then filtered and dried to afford 69-3.

Step 2: To a solution of 69-3 (5 g, 29.4 mmol) in DMSO (35 mL) was addedCs₂CO₃ (47.88 g, 146.9 mmol) and methylamine hydrochloride (5.95 g, 88.2mmol). The mixture was stirred at 120° C. overnight. The mixture waspoured into water, and the solution was extracted with ethyl acetate.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give a residue which was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/1 to 1/4) to afford69-4.

Step 3: To a solution of 69-4 (3.2 g, 15.9 mmol) in toluene (12 mL) wereadded trimethoxymethane (3.54 g, 33.4 mmol) and 4-methylbenzenesulfonicacid (60.5 mg, 0.35 mmol). The solution was stirred at 100° C. for 2hours under N₂ atmosphere. The solvent was removed to give a residue,which was purified by silica gel chromatography (petroleum ether/ethylacetate=5/1 to 1/1) to afford 69-5.

Step 4: A mixture of 69-5 (3.2 g, 16.7 mmol) and Pd/C (10%, 300 mg) inMeOH (10 mL) and THE (30 mL) was stirred at room temperature underhydrogen atmosphere for 6 hours. Then filtered and the filtrate wasconcentrated to afford 69-6.

Step 5: To a solution of 69-6 (2.51 g, 15.5 mmol) in HOAc (25 mL) wasadded bromine (2.5 g, 15.5 mmol). After stirring at room temperature for1 hour, the solution was diluted with H₂O and basified to pH=8 with asaturated sodium bicarbonate solution. The solution was extracted withethyl acetate. The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give a residue which was purified by silicagel column chromatography (petroleum ether/ethyl acetate=1/1 to 1/4) toafford 69-7.

Step 6: To a mixture of 69-7 (1.6 g, 6.6 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.67 g, 10.0mmol) and Cs₂CO₃ (5.41 g, 16.6 mmol) in dioxane (16 mL) and water (3 mL)was added Pd(dppf)Cl₂ (243 mg, 0.33 mmol) under N₂. The mixture wasstirred at 80° C. for 2.5 hours under nitrogen atmosphere. The solutionwas diluted with ethyl acetate and H₂O. The organic layer was dried overNa₂SO₄ and concentrated to give a residue which was purified by silicagel chromatography (petroleum ether/ethyl acetate=1/1 to 1/3) to afford69-8.

Step 7: A mixture of 69-8 (1.1 g, 5.4 mmol) and Pd/C (10%, 100 mg) inethyl acetate (10 mL) was stirred at room temperature under hydrogenatmosphere for 2 hours. Then filtered and the filtrate was concentratedto afford 69-2.

Followed similar steps in example 1 to synthesize 69. LCMS (ESI, m/z):[M+H]⁺=614.1; HNMR (300 MHz, DMSO-d₆, ppm): δ 8.49-8.42 (m, 1H), 8.08(s, 1H), 7.54-7.41 (m, 1H), 7.33-7.13 (m, 4H), 6.94-6.80 (m, 1H), 6.22(d, J=16.4 Hz, 1H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 4.92 (brs, 1H),4.46-4.04 (m, 3H), 3.78 (s, 3H), 3.70-3.05 (m, 3H), 2.78 (d, J=7.1 Hz,1H), 1.98 (s, 3H), 1.43-1.20 (m, 9H). FNMR (282 MHz, DMSO-d₆, ppm): δ−114.52 (1F).

Example 15 Synthesis of Compound 117

Step 1: To a mixture of 6-bromo-4-methylpyridin-2-amine (10 g, 53.5mmol), K₂CO₃ (18.5 g, 133.7 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (11.7 g, 69.5mmol) in dioxane (100 mL) and H₂O (20 mL) was added Pd(dppf)Cl₂ (3.91 g,5.35 mmol) at room temperature under argon atmosphere. The resultingmixture was stirred at 90° C. for 2 hours under argon atmosphere. Thereaction was quenched with water and the mixture was extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=5/1) toafford 117-1.

Step 2: A mixture of 117-1 (6.0 g, 40.5 mmol) and 10% Pd/C (1.2 g) inmethanol (60 mL) was stirred at room temperature overnight underhydrogen atmosphere. The resulting mixture was filtered, and the filtercake was washed with MeOH. The filtrate was concentrated to afford117-2.

Step 3: To a solution of 117-2 (3.0 g, 20 mmol) in H₂SO₄ (35 mL) wasadded fuming HNO₃ (4.5 mL, 71 mmol) dropwise at 0° C. The mixture wasstirred at 50° C. for 2 hours. The reaction was quenched with ice at 0°C. The resulting mixture was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to afford 117-3.

Step 4: A mixture of 117-3 (3.8 g, 15.75 mmol), 10% Pd/C (1.0 g) andhydrazine hydrate (80%, 3.8 mL) in ethyl alcohol (80 mL) was stirred at80° C. for 1.5 hours under argon atmosphere. The mixture was filtered,and the filter cake was washed with acetonitrile. The filtrate wasconcentrated to afford 117-4.

Step 5: A mixture of 117-4 (2.0 g, 9.47 mmol), HCl in MeOH (1 mL, 4.0mmol) and triethyl orthoformate (20 mL) was stirred at 120° C. for 2days under argon atmosphere. The mixture was concentrated to give aresidue which was purified by silica gel column chromatography(petroleum ether/ethyl acetate=10/1) to afford 117-5.

Step 6: A mixture of 117-5 (1.1 g, 4.97 mmol) and 10% Pd/C (354 mg) inMeOH (10 mL) and THF (10 mL) stirred at room temperature overnight underhydrogen atmosphere. The mixture was filtered, the filter cake waswashed with MeOH. The filtrate was concentrated to afford 117-6.

Followed similar steps in example 1 to synthesize 117. LCMS (ESI, m/z):[M+H]⁺=602.4; HNMR (300 MHz, DMSO-d₆, ppm): δ 8.83 (s, 1H), 8.55-8.45(m, 1H), 7.54-7.41 (m, 1H), 7.36-7.13 (m, 3H), 6.96-6.80 (m, 1H), 6.25(d, J=16.8 Hz, 1H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 4.99 (brs, 1H),4.43-4.33 (m, 2H), 4.25-4.00 (m, 1H), 3.83-3.79 (m, 1H), 3.69-3.44 (m,1H), 3.27-3.12 (m, 1H), 2.84-2.78 (m, 1H), 2.20 (d, J=2.4 Hz, 3H), 1.34(d, J=6.6 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.00-0.98 (m, 3H). FNMR (282MHz, DMSO-d₆, ppm): δ −114.30 (1F).

Example 16 Synthesis of Compound 44

Step 1: To a mixture of 2,6-dichloro-5-fluoronicotinic acid (23 g, 0.11mol) in dichloromethane (300 mL) was added dimethylformamide (0.2 mL).Then oxalyl chloride (33 g, 0.26 mol) was added slowly over 30 minutesat room temperature. The mixture was stirred at room temperature for anhour and then concentrated to give an oil which was dissolved in dioxane(50 mL). The solution was added to ammonium hydroxide (150 mL) at 0° C.over 30 minutes. The resulting mixture was stirred at 0° C. for 30minutes and then filtered. The filter cake was washed with cooled water(50 mL) and dried to afford 42-5.

Step 2: A solution of 42-5 (11 g, 52.6 mmol) in 1,2-dichloroethane (80mL) was treated with oxalyl chloride (8.68 g, 68.4 mmol). The mixturewas stirred at 80° C. for 45 minutes and the reaction was concentrated.The residue was dissolved in acetonitrile (100 mL), cooled to −10° C.,and a solution of 1-1 (9.6 g, 55.2 mmol) in THF (30 mL) was then added.The resulting mixture was stirred at room temperature for 2 hours. Thesolution was diluted with a sat. aqueous NaHCO₃ solution and extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by columnchromatography on silica gel (petroleum ether to petroleum ether/ethylacetate=4/1) to afford 42-6.

Step 3: To a stirred solution of 42-6 (7.9 g, 19.3 mmol) in THF (100 mL)at −20° C. was added KHMDS (38.6 mL, 1 M in THF, 38.6 mmol). Theresulting mixture was stirred at room temperature for 2 hours. Thereaction was quenched with sat. aqueous NH₄Cl solution and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate and concentrated. The residue was purified byflash column chromatography on silica gel (petroleum ether to petroleumether/ethyl acetate=2/1) to afford 42-3.

Step 4: To a solution of 42-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol)in MeCN (20 mL) was added POCl₃ (367 mg, 2.4 mmol) dropwise at roomtemperature. The resulting mixture was stirred at 80° C. for 45 minutes,followed by addition of DIEA (3.87 g, 30 mmol) and a solution of 42-2(1.58 g, 4 mmol) in MeCN (10 mL) dropwise at −10° C. After stirring atroom temperature for 1 hour, the reaction was quenched with ice-waterand the mixture was extracted with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by flash column chromatography on silica gel(dichloromethane to dichloromethane/methanol=10/1) to afford 42-4.

Step 5: A mixture of 42-4 (8 mg, 0.15 mmol),3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (42 mg,0.18 mmol), Pd(dppf)Cl₂ (13 mg, 0.018 mmol) and KOAc (40 mg, 0.41 mmol)in dioxane (3 mL)/H₂O (1 drop) was stirred at 80° C. for 2 hours undernitrogen atmosphere. The mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by aPrep-HPLC (acetonitrile with 0.05% of TFA in water (30% to 65%) toafford 44. LCMS (ESI, m/z): [M+H]⁺=599.1; HNMR (400 MHz, methanol-d₄,ppm): δ 8.73 (s, 1H), 8.26-8.22 (m, 1H), 7.15-7.09 (m, 1H), 6.84-6.74(m, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.42-6.38 (m, 1H), 6.30-6.24 (m, 1H),5.83-5.78 (m, 1H), 5.01 (brs, 1H), 4.91-4.83 (m, 1H), 4.53-4.29 (m, 2H),3.96-3.89 (m, 1.5H), 3.54-3.50 (m, 0.5H), 1.82-1.75 (m, 1H), 1.73-1.66(m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.37-1.27 (m, 3H), 1.16-1.05 (m, 4H),1.03-0.97 (m, 2H), 0.88-0.83 (m, 2H). FNMR (376 MHz, methanol-d₄, ppm):δ −114.9 (1F), −125.6 (1F).

Example 17 Synthesis of Compound 126

Step 1: To a suspension of 2,5,6-trichloronicotinic acid (10 g, 44 mmol)in dichloromethane (100 mL) at room temperature was added oxalylchloride (11 g, 88 mmol) and 15 drops of dry DMF. After 30 minutes, theresulting solution was concentrated to give a residue which wasdissolved in dioxane (40 mL). 100 mL of ammonia (28% NH₃ in water) wasadded dropwise at 0° C., and the reaction mixture was allowed to stirfor additional 10 minutes, filtered, and washed with water. The filtercake was collected and freeze-dried to afford 1-2.

Step 2: A solution of 1-2 (550 mg, 2.44 mmol) in DCE (5 mL) was treatedwith oxalyl chloride (464.5 mg, 3.66 mmol). The mixture was stirred at80° C. for 45 minutes and then concentrated. The residue was dissolvedin acetonitrile (5 mL), cooled to −10° C., and a solution of 1-1 (1 g,5.86 mmol) in acetonitrile (5 mL) was added. The resulting mixture wasstirred at room temperature for overnight and then concentrated. Theresidue was purified by flash column chromatography on silica gel (ethylacetate/petroleum ether=1/9 to 1/3) to afford 1-3.

Step 3: To a stirred solution of 1-3 (845 mg, 1.98 mmol) in THF (40 mL)at −20° C. was added KHMDS (5 mL, 1 M in THF, 5.0 mmol). The resultingmixture was then stirred at room temperature for 2 hours. The reactionwas quenched with sat. aqueous NH₄Cl solution and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flash columnchromatography on silica gel (ethyl acetate/petroleum ether=1/9 to 2/1)to afford 1-4.

Step 4: To a solution of 1-4 (1.0 g, 2.56 mmol) and DIEA (1.32 g, 10.25mmol) in MeCN (20 mL) was added POCl₃ (790 mg, 5.12 mmol) dropwise atroom temperature. The resulting solution was stirred at 80° C. for 45minutes, followed by addition of DIEA (6.62 g, 51.25 mmol) and asolution of 42-2 (1.45 g, 5.12 mmol) in MeCN (5 mL) dropwise at −10° C.After stirring at room temperature for 1 hour, the reaction was thenquenched with ice-water and the mixture was extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated. The residue was purified by flash columnchromatography on silica gel (ethyl acetate/petroleum ether=0/1 to 3/1)to afford 126-1.

Step 5: A mixture of 126-1 (120 mg, 0.22 mmol),3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (104 mg,0.44 mmol), Pd(dppf)Cl₂ (16 mg, 0.022 mmol) and KOAc (108 mg, 1.11 mmol)in dioxane (3 mL)/H₂O (1 drop) was stirred at 80° C. for 2 hours undernitrogen atmosphere. The mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by aPrep-HPLC (acetonitrile with 0.05% of TFA in water (34% to 45%) toafford 126. LCMS (ESI, m/z): [M+H]⁺=615.3; HNMR (400 MHz, DMSO-d₆, ppm):δ 8.74 (s, 1H), 8.52-8.35 (m, 1H), 7.16-7.07 (m, 1H), 6.94-6.76 (m, 1H),6.51 (d, J=6.0 Hz, 1H), 6.38 (t, J=6.6 Hz, 1H), 6.20 (dd, J=12.6, 1.8Hz, 1H), 5.76 (dd, J=12.6, 1.6 Hz, 1H), 4.91-4.80 (m, 2H), 4.51-3.50 (m,6H), 1.91-1.65 (m, 1H), 1.45-1.15 (m, 6H), 1.10-0.70 (m, 8H). FNMR (376MHz, DMSO-d₆, ppm): δ −114.30 (1F).

Example 18 Synthesis of Compound 127

Step 1: A mixture of 126-1 (200 mg, 0.37 mmol),2-fluoro-6-hydroxyphenylboronic acid (115 mg, 0.74 mmol), Pd(dppf)Cl₂(27 mg, 0.037 mmol) and KOAc (181 mg, 1.85 mmol) in dioxane (3 mL)/H₂O(1 drop) was stirred at 80° C. for 2 hours under nitrogen atmosphere.The mixture was diluted with water and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by a Prep-HPLC (acetonitrile with0.05% of TFA in water: 25% to 48%) to afford 127. LCMS (ESI, m/z):[M+H]⁺=616.2; HNMR (300 MHz, DMSO-d₆, ppm): δ 10.16 (s, 1H), 8.71 (s,1H), 8.50-8.40 (m, 1H), 7.31-7.23 (m, 1H), 6.86-6.67 (m, 3H), 6.20 (d,J=16.5 Hz, 1H), 5.79-5.74 (m, 1H), 4.99-4.78 (m, 1.5H), 4.55-4.45 (m,0.5H), 4.40-4.05 (m, 1.5H), 3.95-3.68 (m, 2H), 3.55-3.45 (m, 0.5H),1.80-1.60 (m, 2H), 1.34 (s, 3H), 1.30-1.23 (m, 3H), 0.95 (d, J=5.7 Hz,2H), 0.90 (s, 4H), 0.82 (s, 2H). FNMR (282 MHz, DMSO-d₆, ppm): δ −115.33(1F).

Example 19 Synthesis of Compound 124

Step 1: To a solution of 8-1 (900 mg, 2.3 mmol) and DIEA (1.2 g, 9.3mmol) in MeCN (3 mL) was added POCl₃ (707 mg, 4.6 mmol) dropwise at roomtemperature. The resulting solution was stirred at 80° C. for 45minutes, followed by addition of DIEA (6.62 g, 51.25 mmol) and asolution of 8-1 (889 mg, 5.8 mmol) in MeCN (2 mL) dropwise at −10° C.After stirring at room temperature for 1 hour, the reaction was quenchedwith ice-water and the mixture was extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by flash column chromatography onsilica gel (ethyl acetate/petroleum ether=0/1 to 3/1) to afford 124-1.

Step 2: A mixture of 124-1 (170 mg, 0.32 mmol),3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (153 mg,0.64 mmol), Pd(dppf)Cl₂ (36 mg, 0.048 mmol) and KOAc (158 mg, 1.61 mmol)in dioxane (3 mL)/H₂O (1 drop) was stirred at 80° C. for 2 hours undernitrogen atmosphere. The mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by aPrep-HPLC (10 mM aqueous NH₄HCO₃ with acetonitrile (26% to 42%)) toafford 124. LCMS (ESI, m/z): [M+H]⁺=601.4; HNMR (300 MHz, DMSO-d₆, ppm):δ 8.74 (s, 1H), 8.52-8.35 (m, 1H), 7.19-7.07 (m, 1H), 6.86-6.80 (m, 1H),6.51 (d, J=8.1 Hz, 1H), 6.38 (t, J=9.0 Hz, 1H), 6.22 (d, J=16.8 Hz, 1H),5.78 (dd, J=10.5, 2.4 Hz, 1H), 5.22 (brs, 2H), 5.12-4.96 (m, 1H),4.49-4.29 (m, 1H), 4.20-4.03 (m, 1H), 3.71-3.64 (m, 1H), 3.25-3.17 (m,1H), 1.90-1.75 (m, 2H), 1.35 (dd, J=23.7, 6.4 Hz, 3H), 1.15-0.75 (m,8H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.17 (1F).

Example 20 Synthesis of Compound 151 and Compound 152

Followed similar steps in example 1 to synthesize 151-1. 151-1 (1.7 g)was purified by SFC (Dr. Maisch MIC, 250×25 mm, 10 μm, 55% MeOH/CO₂, 70mL/min, 100 bar) to obtain two peaks: 151-1-P1 (peak 1, 623 mg, 98.1%ee) and 151-1-P2 (peak 2, 756 mg, >99% ee).

Followed similar steps in example 1 to synthesize 151. LCMS (ESI, m/z):[M+H]⁺=629.3; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.45-8.40 (m, 1H), 8.07(s, 1H), 7.27 (s, 1H), 7.01 (dd, J=15.2, 8.0 Hz, 1H), 6.90-6.86 (m, 1H),6.40 (d, J=8.0 Hz, 1H), 6.34-6.18 (m, 2H), 5.77 (dd, J=10.4, 2.4 Hz,1H), 5.07-5.02 (m, 2H), 4.92 (s, 1H), 4.44-4.41 (m, 0.5H), 4.32-4.15 (m,2H), 4.08-4.04 (m, 0.5H), 3.84-3.61 (m, 4.5H), 3.50-3.47 (m, 0.5H),3.18-3.01 (m, 1H), 2.92-2.86 (m, 0.5H), 2.74-2.70 (m, 0.5H), 2.01 (s,2H), 1.88 (s, 1H), 1.35-1.18 (m, 9H).

Followed similar steps in example 1 to synthesize 152. LCMS (ESI, m/z):[M+H]⁺=629.1; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.40 (s, 1H), 8.06 (s,1H), 7.27 (s, 1H), 7.01 (dd, J=15.2, 7.9 Hz, 1H), 6.95-6.80 (m, 111),6.40 (d, J=8.2 Hz, 1H), 6.29 (t, J=8.8 Hz, 1H), 6.21 (d, J=16.4 Hz, 1H),5.77 (dd, J=10.4, 2.3 Hz, 1H), 5.04 (s, 2H), 4.89 (s, 1H), 4.47-3.99 (m,3H), 3.85-3.39 (m, 5H), 3.21-3.01 (m, 1H), 2.91-2.63 (m, 1H), 2.05-1.86(m, 3H), 1.39-1.14 (m, 9H).

Example 21 Synthesis of Compound 157 and Compound 158

Step 1: To a mixture of 2-chloro-6-methyl-3-nitropyridine (25 g, 144.5mmol) and K₂CO₃ (59.8 g, 433.5 mmol) in DMSO (200 mL) was addedmethylamine hydrochloride (11.8 g, 173.4 mmol) dropwise. After stirringat room temperature for overnight, the reaction mixture was diluted withwater and extracted with ethyl acetate. The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated to afford 157-1.

Step 2: A solution of 157-1 (23.3 g, 139.5 mmol) and N-bromosuccinimide(26 g, 146.5 mmol) in DMF (250 mL) was stirred for 2 hours at roomtemperature. The reaction mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated to afford 157-2.

Step 3: A mixture of 157-2 (32 g, 131 mmol), Zn power (85 g, 1310 mmol),a solution of NH₄Cl (34.7 g, 655 mmol) in water (30 mL) anddichloromethane/methanol (1/1, 150 mL) was stirred at room temperaturefor 2 hours under N₂ atmosphere. Filtered and the filter cake was washedwith dichloromethane. The combined filtrates were diluted with water andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated to afford157-3.

Step 4: A solution of 157-3 (19.3 g, 89.8 mmol) and p-toluenesulfonicacid monohydrate (1.7 g, 8.97 mmol) in triethyl orthoformate (150 mL)was stirred at 100° C. for 2 hours under N₂ atmosphere. The resultingmixture was diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and concentrated to give a residue which was purified by silicagel chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to afford157-4.

Step 5: A mixture of 157-4 (11 g, 48.9 mmol), diphenylmethanimine (13.3g, 73.3 mmol), cesium carbonate (31.9 g, 97.8 mmol), Pd₂(dba)₃ (2.23 g,2.44 mmol) and Xantphos (2.83 g, 4.88 mmol) in DMF (100 mL) was stirredat 120° C. for overnight under N₂ atmosphere. The resulting mixture wascooled, diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give a residue which was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1 to 1/5) to afford157-5.

Step 6: To a solution of 157-5 (12.80 g, 39.26 mmol) in dichloromethane(60 mL) was added a solution of HCl in dioxane (4 M, 30 mL) dropwise.The mixture was stirred at room temperature for 1 hour. To the solutionwas added acetonitrile (30 mL), and filtered to afford 157-6.

Step 7: To a solution of 157-6 (8.8 g, 54.3 mmol) in acetic acid (150mL) was added Br₂ (8.7 g, 54.3 mmol) dropwise. The mixture was stirredat room temperature for 2 hours under N₂ atmosphere. The resultingsolution was adjusted to pH=7-8 with a saturated sodium bicarbonatesolution. The mixture was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to give a residue which was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1 to 1/5) to afford157-7.

Step 8: A mixture of 157-7 (6.3 g, 26.25 mmol),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.93 g, 47.25mmol), potassium carbonate (9.1 g, 65.6 mmol) and Pd(dppf)Cl₂ (1.54 g,2.1 mmol) in 1,4-dioxane (60 mL) and H₂O (12 mL) was stirred at 80° C.overnight under N₂ atmosphere. The mixture was cooled, diluted withwater and extracted with ethyl acetate. The organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated to givea residue which was purified by silica gel chromatography (petroleumether/ethyl acetate=10/1 to 1/1) to afford 157-8.

Step 9: A mixture of 157-8 (4.5 g, 22.28 mmol) and 10% Pd/C (0.45 g) intetrahydrofuran (50 mL) was stirred at room temperature overnight underhydrogen atmosphere. The mixture was filtered and the solid was washedwith tetrahydrofuran. The filtrate was concentrated to afford 157-9.

Followed similar steps in example 1 to synthesize 157-10. 157-10 (1.15g) was purified by SFC (Dr. Maisch MIC, 250×25 mm, 10 μm, 40% EtOH/CO₂,70 mL/min, 100 bar) to give two peaks: 157-10-P1 (peak 1, 523 mg, >99%ee) and 157-10-P2 (peak 2, 578 mg, >99% ee).

Followed similar steps in example 1 to synthesize 157. LCMS (ESI, m/z):[M+H]⁺=614.6; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.40-8.25 (m, 2H), 7.06(dd, J=15.0, 8.1 Hz, 1H), 6.95-6.80 (m, 1H), 6.42 (d, J=8.2 Hz, 1H),6.37-6.30 (m, 1H), 6.22 (d, J=16.8 Hz, 1H), 5.77 (dd, J=10.4, 2.2 Hz,1H), 5.29 (s, 2H), 4.95 (s, 1H), 4.45-4.41 (m, 0.5H), 4.31-4.28 (m,1.5H), 4.17 (d, J=11.6 Hz, 0.5H), 4.04 (d, J=13.0 Hz, 0.5H), 3.81 (s,3H), 3.75-3.59 (m, 1H), 3.53-3.46 (m, 1H), 3.11 (t, J=11.3 Hz, 1H),2.85-2.70 (m, 1H), 2.16 (s, 3H), 1.34 (d, J=6.8 Hz, 6H), 1.24 (d, J=6.9Hz, 3H).

Followed similar steps in example 1 to synthesize 158. LCMS (ESI, m/z):[M+H]⁺=614.2; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.40-8.25 (m, 2H), 7.06(dd, J=15.0, 8.2 Hz, 1H), 6.94-6.81 (m, 1H), 6.42 (d, J=8.2 Hz, 1H),6.37-6.31 (m, 1H), 6.21 (dd, J=16.2, 4.6 Hz, 1H), 5.77 (dd, J=10.4, 2.2Hz, 1H), 5.29 (s, 2H), 4.90 (s, 1H), 4.45-4.41 (m, 0.5H), 4.31-4.28 (m,1.5H), 4.17 (d, J=11.6 Hz, 0.5H), 4.04 (d, J=13.0 Hz, 0.5H), 3.81 (s,3H), 3.72-3.68 (m, 1.5H), 3.49-3.33 (m, 0.5H), 3.12 (t, J=12.0 Hz, 1H),2.82-2.72 (m, 1H), 2.15 (s, 3H), 1.35 (d, J=6.8 Hz, 6H), 1.24 (d, J=6.8Hz, 3H).

Example 22 Synthesis of Compound 145 and Compound 146

Step 1: To a solution of 1,5-difluoro-2,4-dinitrobenzene (50.0 g. 245mmol) and DCM (500 mL) was added triethylamine (49.5 g, 490 mmol) at 0°C., followed by methylamine hydrochloride (16.5 g, 245 mmol) inportions. The resulting solution was stirred at 0° C. for 2 hours. Water(1 L) and ethyl acetate (1 L) were added. The aqueous layer wasseparated and extracted with ethyl acetate. The organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated to givea residue which was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford 145-1.

Step 2: To a solution of 145-1 (34.0 g, 158 mmol) in ethyl acetate (500mL) was added 10% Pd(OH)₂/C (3.4 g). The resulting mixture was stirredat room temperature overnight under hydrogen atmosphere. Filtered andthe filter cake was washed with ethyl acetate. The filtrate wasconcentrated to afford 145-2.

Step 3: A mixture of 145-2 (19 g, 122 mmol), triethyl orthoformate (36.1g, 244 mmol) and p-toluenesulfonic acid monohydrate (2.32 g, 12.2 mmol)in tetrahydrofuran (200 mL) was refluxed for 2 hours. The mixture wascooled, diluted with water and extracted with ethylacetate/tetrahydrofuran (1/1). The organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated to give a residue whichwas purified by silica gel chromatography (petroleum ether/ethylacetate=1/3) to afford 145-3.

Step 4: To a solution of 145-3 (9 g, 54.5 mmol) in dichloromethane (100mL) was added N-bromosuccinimide (9.7 g, 54.5 mmol) in portions at 0° C.The resulting solution was allowed to warm to room temperature andstirred for 1 hour. The mixture was diluted with water and extractedwith dichloromethane. The organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated to give a residue which waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/2) to afford 145-4.

Step 5: A mixture of 145-4 (5.95 g, 23.4 mmol),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.14 g, 36.6mmol), potassium carbonate (8.07 g, 58.5 mmol) and Pd(dppf)Cl₂ (1.71 g,2.34 mmol) in dioxane (60 mL) and H₂O (12 mL) was stirred at 90° C.overnight under argon atmosphere. The mixture was cooled, diluted withwater and extracted with ethyl acetate. The organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated to givea residue which was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to afford 145-5.

Step 6: A mixture of 145-5 (2.53 g, 12.3 mmol) and 10% Pd/C (0.25 g) intetrahydrofuran (50 mL) was stirred at room temperature overnight underhydrogen atmosphere. The mixture was filtered and the solid was washedwith tetrahydrofuran. The filtrate was concentrated to afford 145-6.

Followed similar steps in example 1 to synthesize 145-7. 145-7 (1.08 g)was purified by SFC (Dr. Maisch MIC, 250×25 mm, 10 m, 50% MeOH/CO₂, 80mL/min, 100 bar) to give two peaks: 145-7-P1 (peak 1, 600 mg, >99% ee)and 145-7-P2 (peak 2, 326 mg, >99% ee).

Followed similar steps in example 1 to synthesize 145. LCMS (ESI, m/z):[M+H]⁺=631.4; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.28-8.20 (m, 1H), 8.20(s, 1H), 7.43 (d, J=9.6 Hz, 1H), 7.08 (dd, J=15.2, 8.0 Hz, 1H),6.91-6.78 (m, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.37 (t, J=8.0 Hz, 1H), 6.19(d, J=16.8 Hz, 1H), 5.77-5.74 (m, 1H), 5.35 (s, 2H), 4.85-4.72 (m,1.5H), 4.50-4.47 (m, 0.5H), 4.25-4.15 (m, 1.5H), 3.91-3.70 (m, 5H),3.50-3.42 (m, 0.5H), 2.94-2.89 (m, 1H), 1.47-1.08 (m, 12H).

Followed similar steps in example 1 to synthesize 146. LCMS (ESI, m/z):[M+H]⁺=631.3; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.33 (d, J=9.6 Hz, 1H),8.20 (s, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.09 (dd, J=15.2, 8.0 Hz, 1H),6.90-6.79 (m, 1H), 6.45 (d, J=8.0 Hz, 1H), 6.37 (t, J=8.0 Hz, 1H), 6.19(dd, J=16.8, 2.0 Hz, 1H), 5.76-5.74 (m, 1H), 5.37 (s, 2H), 4.90-4.82 (m,1H), 4.79-4.74 (m, 0.5H), 4.49-4.45 (m, 0.5H), 4.18-4.02 (m, 1.5H),3.99-3.66 (m, 5H), 3.58-3.54 (m, 1H), 3.04-2.99 (m, 1H), 1.50-0.95 (m,12H).

Example 23 Synthesis of Compound 179 and Compound 180

Step 1: A mixture of 145-4 (1 g, 4.1 mmol), cyclopropylboronic acid (2.8g, 32.9 mmol), Pd(dtbpf)Cl₂ (270 mg, 0.4 mmol) and K₂CO₃ (1.4 g, 10.1mmol) in dioxane (50 mL) and water (10 mL) was stirred at 90° C.overnight under nitrogen atmosphere. The mixture was cooled, andconcentrated to give a residue which was purified by a reverse phaseHPLC (acetonitrile with 0.05% TFA in water: 18% to 20%) to afford 179-1.

Followed similar steps in example 1 to synthesize 179-2. 179-2 (1.34 g)was purified by SFC (Dr. Maisch MIC, 250×25 mm, 10 μm, 55% MeOH/CO₂, 100mL/min, 100 bar) to give two peaks: 179-2-P1 (peak 1, 560 mg, >99% ee)and 179-2-P2 (peak 2, 730 mg, >99% ee).

Followed similar steps in example 1 to synthesize 179. LCMS (ESI, m/z):[M+H]⁺=629.3; HNMR (400 MHz, DMSO-d₆, ppm): δ 8.30 (d, J=9.6 Hz, 1H),8.12 (s, 1H), 7.34 (d, J=9.6 Hz, 1H), 7.10-7.04 (m, 1H), 6.86-6.75 (m,1H), 6.43 (d, J=8 Hz, 1H), 6.38-6.32 (m, 1H), 6.18-6.13 (m, 1H),5.74-5.70 (m, 1H), 5.43 (s, 2H), 4.91-4.70 (m, 2H), 4.50-4.40 (m, 0.5H),4.12-4.06 (m, 1.5H), 3.86-3.82 (m, 2H), 3.77 (s, 3H), 1.70-1.66 (m, 1H),1.49-1.46 (m, 2H), 1.29-1.27 (m, 3H), 1.23-1.13 (m, 3H), 0.79-0.75 (m,1H), 0.68-0.66 (m, 1H). FNMR (376 MHz, DMSO-d₆, ppm): δ −113.81 (HF),−126.99 (F), −127.16 (1F).

Followed similar steps in example 1 to synthesize 180 as TFA salt. LCMS(ESI, m/z): [M+H]⁺=629.3; HNMR (400 MHz, MeOD-d₄, ppm): δ 9.24 (s, 1H),8.26-8.21 (m, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.10-7.05 (m, 1H), 6.90-6.70(m, 1H), 6.42 (d, J=8.4 Hz, 1H), 6.37-6.25 (m, 2H), 5.84-5.79 (m, 6H),5.03-4.90 (m, 2H), 4.61-4.56 (i, 1H), 4.50-4.32 (m, 1H), 4.06 (s, 3H),3.91-3.86 (m, 2H), 1.95-1.85 (m, 1H), 1.53-1.50 (m, 3H), 1.39-1.30 (m,3H), 0.94-0.81 (m, 3H), 0.55-0.53 (m, 1H). FNMR (376 MHz, DMSO-d₆, ppm):δ −116.28 (1F), −123.46 (1F), −126.84 (1F).

Compounds of Formulae (I) and (II) can be prepared by following thesynthetic methods described herein. Table 1 lists representativeanalytical data for some of compounds prepared similarly to theprocesses described in Examples 1-23.

TABLE 1 Characterization of the compounds of Formulas (I) and (II)Compound No. Structure [M + H]⁺ ¹H-NMR and ¹⁹F-NMR 2

615.3 HNMR (300 MHz, DMSO-d₆, ppm): δ 9.07 (s, 1H), 8.67 (s, 1H),7.57-7.46 (m, 1H), 7.37-7.28 (m, 2H), 7.18 (t, J = 7.1 Hz, 1H),7.03-6.78 (m, 1H), 6.24 (d, J = 15.4 Hz, 1H), 5.82 (d, J = 10.6 Hz, 1H),4.94 (brs, 1H), 4.52- 4.28 (m, 2H), 4.15-3.55 (m, 3H), 3.45-3.25 (m,1H), 3.19-2.95 (m, 2H), 2.87-2.77 (m, 1H), 2.71-2.60 (m, 1H), 1.13-1.05(m, 6H), 0.99-0.88 (m, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.71(1F). 3

623.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 11.81 (s, 1H), 8.67 (s, 1H), 8.45(s, 1H), 7.37-7.35 (m, 1H), 7.32-7.28 (m, 1H), 6.93-6.87 (m, 1H),6.84-6.79 (m, 1H), 6.22 (d, J = 17.2 Hz, 1H), 5.78 (dd, J = 10.4, 2.4Hz, 1H), 5.00 (brs, 1H), 4.44-4.34 (m, 2H), 4.30 (s, 2H), 4.21-4.05 (m,1H), 3.85-3.81 (m, 1H), 3.67-3.64 (m, 1H), 3.16-3.10 (m, 1H), 1.78 (brs,2H), 1.36 (d, J = 6.8 Hz, 3H), 0.97- 0.86 (m, 8H). 4

587.1 HNMR (400 MHz, DMSO-d₆ ppm): δ 8.66 (s, 1H), 8.48-8.47 (m, 2H),7.85 (t, J = 8.8 Hz, 1H), 7.60-7.56 (m, 1H), 6.85-6.79 (m, 1H),6.21-6.15 (m, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.94 (brs, 1H),4.38-4.11 (m, 3H), 3.62-3.42 (m, 2H), 3.22-3.07 (m, 1H), 1.73-1.68 (m,2H), 1.31 (d, J = 8.0 Hz, 3H), 0.96-0.72 (m, 8H). FNMR (376 MHz,DMSO-d₆, ppm): δ −123.33 (1F). 5

611.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.69 (s, 1H), 8.60 (s, 1H),7.53-7.49 (m, 1H), 7.32-7.28 (m, 3H), 6.85-6.78 (m, 1H), 6.19 (dd, J =16.8, 2.0 Hz, 1H), 5.77 (d, J = 11.6 Hz, 1H), 4.90 (brs, 1H), 4.34-4.31(m, 3H), 3.93-3.92 (m, 1H), 3.75-3.73 (m, 1H), 3.57-3.53 (m, 1H),3.25-2.98 (m, 2H), 1.80-1.79 (m, 1H), 1.66-1.65 (m, 1H), 0.96-0.80 (m,8H). 7

645.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.41-8.39 (m, 1H), 7.53-7.47 (m,1H), 7.32-7.26 (m, 2H), 7.19-7.15 (m, 1H), 6.88-6.77 (m, 1H), 6.20-6.15(m, 1H), 5.73 (dd, J = 10.4, 2.0 Hz, 1H), 4.97-4.86 (m, 1H), 4.37-4.25(m, 2H), 4.13-3.97 (m, 5H), 3.38-3.04 (m, 3H), 2.35- 2.22 (m, 4H), 1.29(d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.4 Hz, 6H), 0.82 (d, J = 6.8 Hz, 6H).FNMR (376 MHz, DMSO-d₆, ppm): δ −114.91 (1F). 9

604.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.47-8.40 (m, 1H), 7.50-7.45 (m,1H), 7.30-7.23 (m, 2H), 7.16-7.12 (m, 1H), 6.87-6.78 (m, 1H), 6.19-6.15(m, 1H), 5.73 (dd, J = 10.4, 2.0 Hz, 1H), 4.97-4.90 (m, 1H), 4.37-4.23(m, 2H), 4.13-3.98 (m, 1H), 3.85-3.60 (m, 2H), 3.24- 3.05 (m, 1H),2.69-2.59 (m, 2H), 2.55 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H), 1.02 (d, J =6.8 Hz, 6H), 0.87 (d, J = 6.4 Hz, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ−114.81 (1F). 11

619.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.45-8.36 (m, 1H), 7.52-7.46 (m,1H), 7.32-7.25 (m, 2H), 7.20-7.15 (m, 1H), 7.06-6.73 (m, 2H), 6.20-6.15(m, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.99-4.83 (m, 1H), 4.38-4.24(m, 2H), 4.13-3.97 (m, 1H), 3.80-3.40 (m, 2H), 3.23- 3.03 (m, 1H), 2.76(s, 3H), 2.46-2.38 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H), 1.04-0.96 (m, 6H),0.90-0.79 (m, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.83 (1F). 12

633.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.45-8.36 (m, 1H), 7.48-7.43(m, 1H), 7.24-7.20 (m, 2H), 7.18-7.13 (m, 1H), 6.87-6.76 (m, 1H), 6.29(dd, J = 16.4, 4.4 Hz, 1H), 5.81 (dd, J = 10.8 Hz, 2.0 Hz, 1H),5.15-4.97 (m, 1H), 4.54-4.38 (m, 2H), 4.19-4.04 (m, 1H), 3.87-3.56 (m,2H), 3.40-3.32 (m, 1H), 3.17 (s, 6H), 2.56-2.42 (m, 2H), 1.46 (d, J =4.4 Hz, 3H), 1.11 (d, J = 6.4 Hz, 6H), 0.93 (d, J = 6.8 Hz, 6H). FNMR(376 MHz, DMSO-d₆, ppm): δ −115.63 (1F). 14

674.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.76 (br s, 2H), 8.43-8.41 (m,1H), 7.53-7.47 (m, 1H), 7.33-7.25 (m, 2H), 7.20-7.15 (m, 1H), 6.88-6.78(m, 1H), 6.20-6.15 (m, 1H), 5.73 (dd, J = 10.4, 2.0 Hz, 1H), 4.97-4.86(m, 1H), 4.37-4.25 (m, 2H), 4.13-3.93 (m, 5H), 3.81-3.52 (m, 2H),3.31-3.01 (m, 5H), 2.54-2.47 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H), 1.01 (d,J = 6.8 Hz, 6H), 0.85 (d, J = 6.4 Hz, 6H). FNMR (376 MHz, DMSO-d₆, ppm):δ −115.08 (1F). 16

678.4 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.48-8.47 (m, 1H), 7.60-7.49 (m,1H), 7.32 (m, 2H), 7.25-7.16 (m, 1H), 6.88 (m, 1H), 6.22 (m, 1H), 5.78(dd, J = 10.4, 2.4 Hz, 1H), 4.98 (brs, 1H), 4.35-4.69 (m, 2H), 4.08 (m,4H), 3.81 (m, 1H), 3.72-3.42 (m, 1H), 3.18 (m, 1H), 2.78-2.56 (m, 2H),1.35 (d, J = 6.6 Hz, 3H), 1.20 (s, 6H), 1.07 (d, J = 6.6 Hz, 6H), 0.92(d, J = 6.6 Hz, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.70 (1F). 21

657.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 9.51 (brs, 1H), 8.35-8.25 (m, 1H),7.58-7.54 (m, 1H), 7.41-7.30 (m, 3H), 6.85-6.81 (m, 1H), 6.17 (d, J =16.8 Hz, 1H), 5.74 (dd, J = 10.8, 2.0 Hz, 1H), 4.90 (brs, 1H), 4.50-4.48(m, 2H), 4.28-3.98 (m, 3H), 3.70-3.57 (m, 2H), 3.45-3.23 (m, 2H),3.20-3.12 (m, 1H), 2.82 (d, J = 4.0 Hz, 6H), 1.69 (brs, 2H), 1.30 (d, J= 6.8 Hz, 3H), 0.99-0.78 (m, 8H). FNMR (376 MHz, DMSO-d₆, ppm): δ−113.74 (1F), −129.25 (1F). 22

693.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.45-8.44 (m, 1H), 7.24-7.18(m, 1H), 6.87-6.77 (m, 1H), 6.64-6.55 (m, 2H), 6.30 (dd, J = 16.8, 2.0Hz, 1H), 5.81 (dd, J = 10.8, 2.0 Hz, 1H), 5.08 (brs, 1H), 4.74 (t, J =4.8 Hz, 2H), 4.53-4.39 (m, 2H), 4.20-4.05 (m, 1H), 4.09-4.05 (m, 1H),3.87-3.85 (m, 1H), 3.74-3.63 (m, 1H), 3.59 (t, J = 4.8 Hz, 2H),3.37-3.29 (m, 1H), 2.97 (s, 6H), 2.75- 2.70 (m, 2H), 1.48 (d, J = 6.4Hz, 3H), 1.15 (d, J = 6.8 Hz, 6H), 1.00 (d, J = 6.8 Hz, 6H). FNMR (376MHz, methanol-d₄, ppm): δ −117.41 (1F). 23

692.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.47-8.44 (m, 1H), 7.11-7.05(m, 1H), 6.84-6.81 (m, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.35-6.28 (m, 2H),5.82 (dd, J = 10.8, 2.0 Hz, 1H), 5.12-5.04 (m, 1H), 4.76-4.73 (m, 2H),4.53- 4.38 (m, 2H), 4.21-4.06 (m, 1H), 3.91-3.83 (m, 1H), 3.74-3.61 (m,1H), 3.60-3.58 (m, 2H), 3.28-3.26 (m, 1H), 2.97 (s, 6H), 2.82-2.79 (m,1H), 2.62-2.59 (m, 1H), 1.48-1.46 (m, 3H), 1.18-1.13 (m, 6H), 1.07 (d, J= 6.4 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H). FNMR (376 MHz, methanol-d₄,ppm): δ −117.38 (1F). 24

691.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.47-8.45 (m, 1H), 7.51-7.45(m, 1H), 7.22-7.14 (m, 3H), 6.88-6.74 (m, 1H), 6.31-6.25 (m, 1H),5.83-5.78 (m, 1H), 5.02- 5.01 (m, 1H), 4.75-4.73 (m, 2H), 4.53-4.29 (m,2H), 3.98-3.90 (m, 2H), 3.59 (t, J = 4.8 Hz, 2H), 3.01-3.00 (m, 1H),2.97 (s, 6H), 2.78-2.64 (m, 2H), 1.50-1.27 (m, 6H), 1.17-1.14 (m, 6H),1.02-0.98 (m, 6H), FNMR (376 MHz, methanol-d₄, ppm): δ −116.00 (1F). 27

584.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.32-8.26 (m, 1H), 7.57-7.51 (m,1H), 7.38-7.30 (m, 3H), 6.81-6.77 (m, 1H), 6.20-6.15 (m, 1H), 5.72 (dd,J = 10.4, 2.0 Hz, 1H), 4.97-4.85 (m, 1H), 4.39-3.97 (m, 3H), 3.77-3.35(m, 2H), 3.29-3.01 (m, 1H), 2.42 (s, 3H), 1.73-1.61 (m, 2H), 1.30 (d, J= 6.8 Hz, 3H), 0.98-0.89 (m, 4H), 0.87- 0.72 (m, 4H). FNMR (376 MHz,DMSO-d₆, ppm): δ −113.71 (1F), −129.20 (1F). 28

600.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.19 (s, 1H), 8.26-8.21 (m, 1H),7.29-7.23 (m, 1H), 6.87-6.77 (m, 1H), 6.74-6.66 (m, 2H), 6.20-6.15 (m,1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.97-4.85 (m, 1H), 4.39-3.97 (m,3H), 3.71-3.40 (m, 2H), 3.23-3.03 (m, 1H), 2.40 (s, 3H), 1.66-1.56 (m,2H), 1.30 (d, J = 6.4 Hz, 3H), 0.91-0.79 (m, 6H), 0.72-0.67 (m, 2H).FNMR (376 MHz, DMSO- d₆, ppm): δ −115.13 (1F),−128.41 (1F). 29

599.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.31-8.25 (m, 1H), 7.11 (dd, J =14.8, 8.0 Hz, 1H), 6.87-6.77 (m, 1H), 6.50 (d, J = 8.0 Hz, 1H),6.40-6.35 (m, 1H), 6.20-6.15 (m, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H),4.97-4.85 (m, 1H), 4.39-3.97 (m, 3H), 3.73-3.42 (m, 2H), 3.22-3.02 (m,1H), 2.43 (s, 3H), 1.73-1.65 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H),0.91-0.81 (m, 6H), 0.73-0.68 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ−113.98 (1F), −126.93 (1F). 31

691.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.61 (s, 1H), 7.49-7.46 (m,1H), 7.23-7.14 (m, 3H), 6.84-6.77 (m, 1H), 6.28 (dd, J = 16.8, 2.0 Hz,1H), 5.78 (dd, J = 10.8, 2.0 Hz, 1H), 4.75-4.74 (m, 2H), 4.73-4.69 (m,1H), 4.49-4.46 (m, 2H), 3.83-3.78 (m, 2H), 3.61-3.58 (m, 2H), 3.02-2.97(m, 1H), 2.97 (s, 6H), 2.73-2.69 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H),1.18-1.15 (m, 6H), 1.01- 0.99 (m, 611). 32

664.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.44-8.42 (m, 1H), 7.51-7.46 (m,1H), 7.31-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.88-6.79 (m, 1H), 6.20-6.16(m, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.94 (brs, 1H), 4.39-4.37 (m,2H), 4.34-4.24 (m, 2H), 4.14-3.99 (m, 1H), 3.80-3.75 (m, 1H), 3.65-3.59(m, 2H), 3.47-3.41 (m, 1H), 3.26 (s, 3H), 3.21-3.05 (m, 1H), 2.60-2.59(m, 2H), 1.31 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.8 Hz, 6H), 0.87 (d, J= 6.4 Hz, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ −113.74 (1F). 35

627.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.26-8.22 (m, 1H), 7.53-7.43(m, 2H), 7.27-7.18 (m, 2H), 6.84-6.77 (m, 1H), 6.31-6.27 (m, 1H), 5.81(dd, J = 10.8, 2.0 Hz, 1H), 5.07 (brs, 1H), 4.54-4.40 (m, 2H), 4.20-4.05(m, 1H), 3.84-3.81 (m, 1H), 3.73-3.56 (m, 1H), 3.29-3.19 (m, 1H), 2.34(s, 3H), 1.75-1.65 (m, 2H), 1.50-1.45 (m, 3H), 1.18-1.09 (m, 4H),0.96-0.79 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −114.92 (1F),−128.80 (1F). 36

607.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.69 (s, 1H), 8.37-8.32 (m,1H), 7.50-7.43 (m, 2H), 7.36-7.34 (m, 1H), 6.88-6.78 (m, 1H), 6.30 (dd,J = 16.4, 5.2 Hz, 1H), 5.82 (dd, J = 10.8, 2.0 Hz, 1H), 5.10 (brs, 1H),4.51- 4.41 (m, 2H), 4.22-4.06 (m, 1H), 3.91-3.81 (m, 1H), 3.75-3.59 (m,1H), 3.38-3.34 (m, 1H), 1.77-1.75 (m, 2H), 1.50-1.47 (m, 3H), 1.13-1.09(m, 2H), 0.96-0.94 (m, 4H), 0.77-0.76 (m, 2H). FNMR (376 MHz,methanol-d₄, ppm): δ −128.50 (1F). 37

621.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.69 (s, 1H), 8.34 (t, J = 9.6Hz, 1H), 7.50 (d, J = 3.6 Hz, 2H), 7.40- 7.39 (m, 1H), 6.82-6.75 (m,1H), 6.31-6.25 (m, 1H), 5.83-5.79 (m, 1H), 5.04 (brs, 1H), 4.95-4.91 (m,0.5H), 4.52-4.40 (m, 1H), 4.36-4.31 (m, 1H), 4.02-3.91 (m, 2H),3.56-3.52 (m, 0.5H), 1.80-1.68 (m, 2H), 1.50-1.47 (m, 3H), 1.39-1.29 (m,3H), 1.13-1.08 (m, 2H), 0.98- 0.94 (m, 4H), 0.80-0.72 (m, 2H). FNMR (376MHz, methanol-d₄, ppm): δ −128.32 (1F). 38

621.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 11.97 (brs, 1H), 8.67 (s, 1H),8.34 (d, J = 9.6 Hz, 1H), 7.38-7.34 (m, 1H), 7.34-7.30 (m, 1H),7.00-6.98 (m, 1H), 6.82-6.75 (m, 1H), 6.16 (dd, J = 16.8, 2.4 Hz, 1H),5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.56 (s, 2H), 4.33-4.29 (m, 2H), 3.67-3.62 (m, 2H), 1.74-1.69 (m, 2H), 1.39 (d, J = 6.8 Hz, 6H), 0.93-0.84 (m,6H), 0.77-0.72 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ −128.89 (1F). 39

570.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.72 (s, 1H), 8.34-8.28 (m, 1H),7.57-7.51 (m, 1H), 7.36-7.29 (m, 3H), 6.88-6.78 (m, 1H), 6.19-6.15 (m,1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.97-4.87 (m, 1H), 4.39-4.36 (m,1H), 4.30-4.23 (m, 1H), 4.02-3.98 (m, 1H), 3.76-3.67 (m, 1H), 3.61-3.40(m, 1H), 3.23-3.04 (m, 1H), 1.77- 1.66 (m, 2H), 1.31 (d, J = 6.8 Hz,3H), 0.98-0.86 (m, 6H), 0.82-0.77 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm):δ −113.53 (1F), −128.96 (1F). 40

586.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.20 (br s, 1H), 8.68 (s, 1H),8.28-8.22 (m, 1H), 7.25 (dd, J = 15.2, 8.4 Hz, 1H), 6.87-6.78 (m, 1H),6.74-6.65 (m, 2H), 6.19- 6.15 (m, 1H), 5.73 (dd, J = 10.4 Hz, 2.4 Hz,1H), 4.94- 4.86 (m, 1H), 4.39-4.36 (m, 1H), 4.29-4.25 (m, 1H), 4.13-3.98(m, 1H), 3.72-3.66 (m, 1H), 3.62-3.41 (m, 1H), 3.24-3.04 (m, 1H),1.72-1.62 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H), 0.95-0.84 (m, 6H),0.77-0.73 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ −115.16 (1F), −128.10(1F). 41

585.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.73 (s, 1H), 8.32-8.27 (m, 1H),7.10 (dd, J = 15.2, 8.0 Hz, 1H), 6.87- 6.78 (m, 1H), 6.49 (d, J = 8.4Hz, 1H), 6.40-6.35 (m, 1H), 6.19-6.15 (m, 1H), 5.73 (dd, J = 10.4, 2.0Hz, 1H), 4.96-4.85 (m, 1H), 4.39-3.98 (m, 3H), 3.61-3.39 (m, 2H),3.23-3.03 (m, 1H), 1.80-1.70 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H),0.95-0.88 (m, 6H), 0.78-0.73 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ−113.86 (1F), −126.67 (1F). 43

600.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.19 (s, 1H), 8.68 (s, 1H),8.28-8.24 (m, 1H), 7.29-7.23 (m, 1H), 6.87-6.65 (m, 3H), 6.17-6.13 (m,1H), 5.74-5.69 (m, 1H), 4.91-4.72 (m, 1.5H), 4.59-4.51 (m, 0.5H), 4.20-4.05 (m, 1.5H), 3.82-3.75 (m, 2H), 3.49-3.45 (m, 0.5H), 1.68-1.62 (m,2H), 1.30-1.15 (m, 6H) , 0.97-0.72 (m, 8H). FNMR (376 MHz, DMSO-d₆,ppm): δ −115.09 (1F), −127.86 (1F). 45

584.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.72 (s, 1H), 8.34 (d, J = 10.0Hz, 1H), 7.57-7.49 (m, 2H), 7.38-7.30 (m, 2H), 6.80-6.74 (m, 1H), 6.15(dd, J = 16.8, 2.4 Hz, 1H), 5.72 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 4.54(brs, 2H), 4.32-4.28 (m, 2H), 3.66-3.61 (m, 2H), 1.75-1.68 (m, 2H), 1.37(d, J = 6.8 Hz, 6H), 1.00-0.86 (m, 8H). FNMR (376 MHz, DMSO-d₆, ppm): δ−113.40 (1F), −128.61 (1F). 46

600.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.20 (brs, 1H), 8.68 (s, 1H),8.28 (d, J = 9.2 Hz, 1H), 7.28-7.23 (m, 1H), 6.80-6.65 (m, 3H), 6.15(dd, J = 16.8, 2.4 Hz, 1H), 5.71 (dd, J = 10.4. 2.4 Hz, 1H), 4.53 (s,2H), 4.30-4.26 (m, 2H), 3.63-3.58 (m, 2H), 1.70-1.63 (m, 2H), 1.38 (d, J= 6.8 Hz, 6H), 0.96-0.82 (m, 6H), 0.76-0.71 (m, 2H). FNMR (376 MHz,DMSO-d₆, ppm): δ −115.19 (1F), −127.81 (1F). 47

599.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.74 (s, 1H), 8.38 (d, J = 9.2Hz, 1H), 7.16-7.10 (m, 1H), 6.85-6.78 (m, 1H), 6.54 (d, J = 8.4 Hz, 1H),6.43-6.39 (m, 1H), 6.31-6.26 (m, 1H), 5.80 (d, J = 10.4 Hz, 1H), 4.69(s, 2H), 4.50-4.46 (m, 2H), 3.82-3.78 (m, 2H), 1.80-1.73 (m, 2H), 1.49(d, J = 6.8 Hz, 6H), 1.13-1.11 (m, 4H), 1.02-0.98 (m, 2H), 0.87-0.84 (m,2H). FNMR (376 MHz, methanol-d₄, ppm): δ −114.97 (1F), −125.58 (1F). 50

598.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.33-8.28 (m, 1H), 7.58-7.52 (m,1H), 7.40-7.31 (m, 3H), 6.87-6.74 (m, 1H), 6.17-6.13 (m, 1H), 5.74-5.69(m, 1H), 4.84- 4.44 (m, 2H), 4.18-4.10 (m, 1H), 3.82-3.77 (m, 3H), 2.42(s, 3H), 1.66-1.58 (m, 2H), 1.30-1.26 (m, 3H), 1.23-1.14 (m, 3H),0.95-0.73 (m, 8H). FNMR (376 MHz, DMSO-d₆, ppm): δ −113.54 (1F), −128.96(1F). 51

613.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.26-8.21 (m, 1H), 7.13 (dd, J= 14.8, 8.0 Hz, 1H), 6.88-6.74 (m, 1H), 6.54 (d, J = 8.4 Hz, 1H),6.42-6.38 (m, 1H), 6.30-6.24 (m, 1H), 5.83-5.78 (m, 1H), 5.02-4.90 (m,2H), 4.53- 4.29 (m, 2H), 3.97-3.50 (m, 2H), 2.55 (s, 3H), 1.81-1.65 (m,2H), 1.47 (d, J = 6.8 Hz, 3H), 1.37-1.27 (m, 3H), 1.15-1.08 (m, 4H),1.02-0.94 (m, 2H), 0.85-0.72 (m, 2H). FNMR (376 MHz, methanol-d₄, ppm):δ −115.04 (1F), −125.80 (1F). 52

614.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.19 (s, 1H), 8.26-8.23 (m, 1H),7.26 (dd, J = 15.6, 8.4 Hz, 1H), 6.87- 6.67 (m, 3H), 6.17-6.13 (m, 1H),5.70 (dd, J = 10.4, 2.4 Hz, 1H), 4.81-4.45 (m, 2H), 4.16-3.75 (m, 4H),2.40 (s, 3H), 1.60-1.54 (m, 2H), 1.29-1.16 (m, 6H), 0.90-0.77 (m, 6H),0.71-0.69 (m, 2H). FNMR (376 MHz, DMSO- d₆, ppm): δ −115.06 (1F),−128.17 (1F). 53

598.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.37 (d, J = 9.6 Hz, 1H),7.54-7.48 (m, 1H), 7.44-7.40 (m, 1H), 7.26-7.18 (m, 2H), 6.80 (dd, J =16.8, 10.4 Hz, 1H), 6.27 (dd, J = 16.8, 1.6 Hz, 1H), 5.79 (dd, J = 10.4,1.6 Hz, 1H), 4.76-4.58 (m, 2H), 4.50-4.46 (m, 2H), 3.79 (dd, J = 13.6Hz, 5.2 Hz, 2H), 2.54 (s, 3H), 1.75-1.69 (m, 2H), 1.47 (d, J = 6.8 Hz,6H), 1.18-1.05 (m, 4H), 0.98-0.92 (m, 2H), 0.87-0.80 (m, 2H). FNMR (376MHz, methanol-d₄, ppm): δ −114.80 (1F), −128.40 (1F). 54

613.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.37 (d, J = 9.2 Hz, 1H), 7.12(dd, J = 14.8, 8.0 Hz, 1H), 6.80 (dd, J = 16.8 Hz, 10.8 Hz, 1H), 6.54(d, J = 8.4 Hz, 1H), 6.40 (t, J = 9.2 Hz, 1H), 6.27 (dd, J = 16.8, 1.6Hz, 1H), 5.79 (dd, J = 10.8, 1.6 Hz, 1H), 4.76-4.59 (m, 2H), 4.48-4.45(m, 2H), 3.78 (dd, J = 13.6, 4.8 Hz, 2H), 2.55 (s, 3H), 1.76-1.70 (m,2H), 1.47 (d, J = 7.2 Hz, 6H), 1.18-1.06 (m, 4H), 1.00-0.94 (m, 2H),0.85-0.79 (m, 2H). FNMR (376 MHz, methanol-d₄, ppm): δ −115.06 (1F),−125.72 (1F). 55

614.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.34 (d, J = 9.2 Hz, 1H),7.28-7.22 (m, 1H), 6.80 (dd, J = 16.8, 10.8 Hz, 1H), 6.67 (d, J = 8.4Hz, 1H), 6.62 (t, J = 8.8 Hz, 1H), 6.27 (dd, J = 16.8, 2.0 Hz, 1H), 5.78(dd, J = 10.8, 2.0 Hz, 1H), 4.77-4.59 (m, 2H), 4.50-4.42 (m, 2H), 3.78(dd, J = 13.6, 4.8 Hz, 2H), 2.54 (s, 3H), 1.74-1.70 (m, 2H), 1.47 (d, J= 7.2 Hz, 6H), 1.17-1.01 (m, 4H), 0.97- 0.78 (m, 4H). FNMR (376 MHz,methanol-d₄, ppm): δ −116.09 (1F), −127.30 (1F). 19

664.4 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.48 (s, 1H), 7.61-7.46 (m, 1H),7.39-7.25 (m, 2H), 7.20 (m, 1H), 6.88 (m, 1H), 6.22-6.15 (d, J = 16.8Hz, 1H), 5.78 (dd, J = 10.4, 2.4 Hz, 1H), 4.92 (brs, 1H), 4.91-4.89 (d,J = 4.5 Hz, 1H), 4.45-4.25 (m, 2H), 4.20-4.10 (m, 2H), 4.05- 3.95 (m,1H), 3.85-3.72 (m, 1H), 3.70-3.40 (m, 2H), 3.19-3.05 (m, 1H), 2.70-2.56(m, 2H), 1.35 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 1.06 (d, J= 6.6 Hz, 6H), 0.91 (d, J = 6.6 Hz, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ−114.72 (1F). 30

585.1 HNMR (400 MHz, methanol-d₄, ppm): δ 8.29-8.24 (m, 1H), 7.56-7.46(m, 2H), 7.30-7.20 (m, 2H), 6.87-6.77 (m, 1H), 6.31-6.27 (m, 1H), 5.81(dd, J = 10.8, 2.0 Hz, 1H), 5.10-5.05 (m, 1H), 4.48-4.40 (m, 2H),4.20-4.05 (m, 1H), 3.85-3.82 (m, 1H), 3.72-3.54 (m, 1H), 3.33- 3.22 (m,1H), 1.79-1.74 (m, 2H), 1.47 (d, J = 4.4 Hz, 3H), 1.17-0.93 (m, 8H).FNMR (376 MHz, methanol-d₄, ppm): δ −115.1 (1F), −128.6 (1F). 34

668.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.24-8.19 (m, 1H), 7.55-7.49(m, 1H), 7.46-7.42 (m, 1H), 7.27-7.19 (m, 2H), 6.87-6.76 (m, 1H), 6.26(dd, J = 16.8, 4.4 Hz, 1H), 5.79 (dd, J = 10.8, 1.6 Hz, 1H), 5.10-5.01(m, 1H), 4.52-4.41 (m, 2H), 4.45-4.32 (m, 2H), 4.19-4.03 (m, 4H),3.83-3.77 (m, 1H), 3.71-3.54 (m, 1H), 3.30-3.17 (m, 1H), 2.90 (s, 6H),1.60-1.55 (m, 2H), 1.47-1.43 (m, 3H), 1.09-0.99 (m, 4H), 0.85-0.73 (m,4H). FNMR (376 MHz, methanol-d₄, ppm): δ −115.0 (1F), −129.2 (1F). 48

588.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.35-8.30 (m, 1H), 7.55-7.49 (m,1H), 7.34-7.26 (m, 2H), 7.23-7.19 (m, 1H), 6.88-6.79 (m, 1H), 6.20-6.15(m, 1H), 5.73 (dd, J = 10.4, 2.0 Hz, 1H), 4.92 (brs, 1H), 4.38-4.28 (m,3H), 3.70-3.42 (m, 2H), 3.24-3.06 (m, 1H), 2.63 (s, 2H), 2.62 (s, 3H),1.30 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.0 Hz, 6H), 0.88 (d, J = 6.4 Hz,6H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.45 (1F), −129.22 (1F). 49

602.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.28-8.24 (m, 1H), 7.51-7.49(m, 1H), 7.32-7.28 (m, 1H), 7.24-7.16 (m, 2H), 6.81-6.74 (m, 1H),6.31-6.24 (m, 1H), 5.83- 5.78 (m, 1H), 5.08-5.00 (m, 1H), 4.93-4.88 (m,0.5H), 4.52-4.44 (m, 1H), 4.37-4.29 (m, 1H), 4.00-3.89 (m, 2H),3.56-3.51 (m, 0.5H), 2.77-2.67 (m, 5H), 1.47 (d, J = 6.8 Hz, 3H),1.36-1.26 (m, 3H), 1.18-1.15 (m, 6H), 1.01-0.97 (m, 6H). FNMR (376 MHz,methanol-d₄, ppm): δ −115.34 (1F), −128.47 (1F). 77

604.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.18 (s, 1H), 8.30-8.24 (m, 1H),7.26-7.21 (m, 1H), 6.85-6.78 (m, 1H), 6.71-6.63 (m, 2H), 6.19-6.15 (m,1H), 5.73 (dd, J = 10.4, 2.0 Hz, 1H), 4.92 (brs, 1H), 4.38-4.28 (m, 2H),4.01-3.97 (m, 1H), 3.70-3.59 (m, 2H), 3.25-3.07 (m, 1H), 2.59 (s, 2H),2.57 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.0 Hz, 6H), 0.87(d, J = 6.4 Hz, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ −115.82 (1F),−128.85 (1F). 78

603.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.35-8.20 (m, 1H), 7.13-7.07(m, 1H), 6.88-6.77 (m, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.39-6.27 (m, 2H),5.81 (dd, J = 10.4, J = 2.0 Hz, 1H), 5.06 (brs, 1H), 4.54-4.40 (m, 2 H),4.21- 4.05 (m, 1H), 3.88-3.46 (m, 3H), 2.82-2.66 (m, 5H), 1.53-1.45 (m,3H), 1.21-1.11 (m, 6H), 1.09-0.95 (m, 6H). FNMR (376 MHz, methanol-d₄,ppm): δ −115.58 (1F), −126.35 (1F). 18

675.6 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.47 (m, 1H), 7.55-7.50 (m, 1H),7.36-7.30 (m, 2H), 7.25-7.15 (m, 1H), 6.95-6.80 (m, 1H), 6.22 (d, J =16.9 Hz, 1H), 5.77 (dd, J = 10.4, 2.4 Hz, 1H), 5.10-4.95 (m, 2H),4.42-4.03 (m, 3H), 3.77-3.66 (m, 3H), 3.04-2.96 (m, 2H), 2.74- 2.64 (m,2H), 2.29 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.05 (d, J = 6.7 Hz, 6H),0.90 (d, J = 6.8 Hz, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.72 (1F).25

611.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.35-8.25 (m, 1H), 7.34-7.25(m, 1H), 6.97-6.78 (m, 1H), 6.75-6.63 (m, 2H), 6.33 (d, J = 18.3 Hz,1H), 5.85 (dd, J = 10.6, 2.0 Hz, 1H), 5.18-5.06 (m, 1H), 4.57-4.48 (m,2H), 4.25-4.05 (m, 1H), 3.93-3.85 (m, 1H), 3.80-3.60 (m, 1H), 3.30-3.25(m, 1H), 1.88-1.80 (m, 2H), 1.60-1.55 (m, 3H), 1.25-0.89 (m, 8H). 59

582.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 11.85 (s, 1H), 8.51-8.26 (m, 2H),7.39 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 4.8 Hz,1H), 6.97 (dt, J = 6.6, 3.0 Hz, 1H), 6.94-6.84 (m, 1H), 6.22 (d, J =16.2 Hz, 1H), 5.78 (dd, J = 10.4, 2.4 Hz, 1H), 4.95 (brs, 1H), 4.43-4.25(m, 2H), 4.18-4.05 (m, 1H), 3.85-3.60 (m, 1H), 3.54-3.46 (m, 1H),3.20-3.10 (m, 1H), 2.72-2.58 (m, 1H), 2.01 (d, J = 3.0 Hz, 2H),1.47-1.28 (m, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.83 (dd, J = 6.6, 3.6 Hz,3H). FNMR (376 MHz, DMSO-d₆, ppm): δ −129.05 (1F). 60

639.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.30 (brs, 1H), 8.39-8.25 (m,1H), 7.92 (s, 1H), 7.28 (td, J = 8.2, 6.8 Hz, 1H), 6.95-6.80 (m, 1H),6.79-6.65 (m, 2H), 6.22 (d, J = 16.0 Hz, 1H), 5.78 (dd, J = 10.4, 2.4Hz, 1H), 5.05-4.89 (m, 1H), 4.38-4.31 (m, 2H), 4.21-3.99 (m, 1H),3.77-3.44 (m, 2H), 3.40-3.25 (m, 3H), 3.20-3.05 (m, 1H), 2.90-2.80 (m,1H), 2.06 (s, 3H), 1.35 (dd, J = 11.2, 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz,3H), 0.98 (d, J = 6.6 Hz, 3H). FNMR (376 MHz, DMSO-d₆, ppm): δ −115.72(1F), −125.98 (1F). 56

681.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.27 (t, J = 9.6 Hz, 1H),7.52-7.46 (m, 1H), 7.34-7.30 (m, 1H), 7.25- 7.16 (m, 2H), 6.84-6.80 (m,1H), 6.32-6.28 (m, 1H), 5.83-5.80 (m, 1H), 5.12-5.03 (m, 1H), 4.51-4.40(m, 2H), 4.20-4.05 (m, 1H), 3.88-3.80 (m, 1H), 3.74-3.61 (m, 1H), 3.54(s, 3H), 3.52 (s, 3H), 3.37-3.31-3.19 (m, 1H), 2.74-2.68 (m, 2H),1.51-1.42 (m, 3H), 1.19-1.17 (m, 6H), 1.01-0.99 (m, 6H). FNMR (376 MHz,methanol-d₄, ppm): δ −115.37 (1F), −128.78 (1F). 114

635.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.35-8.30 (m, 1H), 7.52-7.47(m, 2H), 7.41-7.37 (m, 1H), 6.89-6.75 (m, 1H), 6.28 (dd, J = 16.8 Hz,4.4 Hz, 1H), 5.83-5.79 (m, 1H), 5.03-4.89 (m, 2H), 4.54-4.31 (m, 2H),4.02- 3.52 (m, 2H), 2.49 (s, 3H), 1.78-1.59 (m, 2H), 1.49-1.47 (m, 3H),1.38-1.28 (m, 3H), 1.12-1.04 (m, 2H), 1.00- 0.86 (m, 4H), 0.77-0.67 (m,2H). FNMR (376 MHz, methanol-d₄, ppm): δ −128.38 (1F). 84

688.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.45-8.42 (m, 1H), 7.51-7.44(m, 1H), 7.24-7.21 (m, 2H), 7.20-7.14 (m, 1H), 6.87-6.73 (m, 1H),6.31-6.24 (m, 1H), 5.83- 5.77 (m, 1H), 5.02-4.86 (m, 1.5H), 4.52-4.27(m, 2H), 4.15-4.09 (m, 4H), 4.03-3.85 (m, 2H), 3.55-3.50 (m, 0.5H),3.29-3.25 (m, 4H), 2.63-2.51 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H),1.35-1.25 (m, 3H), 1.13-1.10 (m, 6H), 0.97-0.93 (m, 6H). FNMR (376 MHz,methanol-d₄, ppm): δ −115.83 (1F). 17

689.1 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.50-8.46 (m, 1H), 7.59-7.48 (m,1H), 7.40-7.15 (m, 3H), 6.93-6.81 (m, 1H), 6.21 (d, J = 16.6 Hz, 1H),5.77 (dd, J = 10.4, 2.3 Hz, 1H), 5.31-5.27 (m, 1H), 4.98 (brs, 1H),4.45- 3.96 (m, 3H), 3.90-3.55 (m, 3H), 3.30-3.05 (m, 1H), 2.89-2.52 (m,5H), 2.40-2.30 (m, 1H), 2.26 (s, 3H), 1.91-1.78 (m, 1H), 1.35 (d, J =6.6 Hz, 3H), 1.07 (t, J = 7.2 Hz, 6H), 0.90 (d, J = 6.8 Hz, 6H). FNMR(282 MHz, DMSO-d₆, ppm): δ −114.82 (1F). 66

617.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 9.32 (s, 1H), 8.51-8.45 (s, 1H),8.04 (s, 1H), 7.51-7.44 (m, 1H), 7.30- 7.16 (m, 3H), 6.93-6.83 (m, 1H),6.22 (d, J = 12 Hz, 1H), 5.81-5.72 (m, 1H), 4.96 (brs, 1H), 4.44-4.28(m, 2H), 4.25-4.01 (m, 1H), 3.88-3.61 (m, 1H), 3.56-3.44 (m, 1H),3.18-3.09 (m, 1H), 2.65-2.58 (m, 1H), 2.31 (s, 3H), 1.36 (t, J = 6.4 Hz,3H), 1.19-1.11 (m, 3H), 1.08- 0.98 (m, 3H). FNMR (376 MHz, DMSO-d₆,ppm): δ −114.25 (1F). 82

690.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.42-8.40 (m, 1H), 7.24-7.18(m, 1H), 6.87-6.77 (m, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.58 (t, J = 8.4Hz, 1H), 6.29 (dd, J = 16.8, 4.0 Hz, 1H), 5.81 (dd, J = 10.4, 1.6 Hz,1H), 5.11-4.99 (m, 1H), 4.57-4.33 (m, 2H), 4.23-3.98 (m, 5H), 3.91- 3.78(m, 1H), 3.76-3.53 (m, 1H), 3.38-3.33 (m, 1H), 3.26-3.18 (m, 4H),2.63-2.47 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.4 Hz, 6H),0.95 (d, J = 6.4 Hz, 6H). FNMR (376 MHz, methanol-d₄, ppm): δ −117.33(1F). 83

689.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.44-8.41 (m, 1H), 7.11-7.05(m, 1H), 6.88-6.77 (m, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.36-6.27 (m, 2H),5.82 (dd, J = 10.4, 2.0 Hz, 1H), 5.13-4.96 (m, 1H), 4.56-4.35 (m, 2H),4.23- 4.02 (m, 5H), 3.94-3.79 (m, 1H), 3.76-3.52 (m, 1H), 3.40-3.32 (m,1H), 3.28-3.24 (m, 4H), 2.72-2.60 (m, 1H), 2.55-2.41 (m, 1H), 1.46 (d, J= 6.4 Hz, 3H), 1.14- 1.08 (m, 6H), 1.03-0.89 (m, 6H). FNMR (376 MHz,methanol-d₄, ppm): δ −116.98 (1F). 61

600.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.31-8.26 (m, 1H), 7.58-7.52 (m,1H), 7.40-7.32 (m, 3H), 6.88-6.78 (m, 1H), 6.19-6.15 (m, 1H), 5.73 (dd,J = 10.4, 2.4 Hz, 1H), 4.95-4.85 (m, 1H), 4.39-4.25 (m, 2H), 4.13-3.95(m, 2H), 3.77 (s, 3H), 3.60-3.03 (m, 2H), 1.70-1.59 (m, 2H), 1.30 (d, J= 6.8 Hz, 3H), 0.96-0.94 (m, 4H), 0.86- 0.76 (m, 4H). FNMR (376 MHz,DMSO-d₆, ppm): δ −113.68 (1F), −129.30 (1F). 62

616.3 HNMR (400 MHz, DMSO-d_(6,) ppm): δ 10.22 (s, 1H), 8.25-8.20 (m,1H), 7.29-7.24 (m, 1H), 6.87-6.80 (m, 1H), 6.77-6.67 (m, 2H), 6.19-6.14(m, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.95-4.85 (m, 1H), 4.39-4.23(m, 2H), 4.12-3.97 (m, 1H), 3.75 (s, 3H), 3.61-3.40 (m, 2H), 3.23-3.03(m, 1H), 1.65-1.55 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H), 0.93-0.90 (m, 2H),0.86-0.83 (m, 4H), 0.73- 0.70 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ−115.13 (1F), −128.47 (1F). 74

615.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.30-8.25 (m, 1H), 7.15-7.09 (m,1H), 6.87-6.78 (m, 1H), 6.51 (d, J = 8.0 Hz, 1H), 6.41-6.36 (m, 1H),6.19-6.15 (m, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.95-4.85 (m, 1H),4.39-4.23 (m, 2H), 4.13-3.98 (m, 1H), 3.78 (m, 3H), 3.70-3.39 (m, 2H),3.22-3.02 (m, 1H), 1.71-1.61 (m, 2H), 1.29 (d, J = 6.4 Hz, 3H),0.94-0.89 (m, 4H), 0.87-0.72 (m, 4H). FNMR (376 MHz, DMSO-d₆, ppm): δ−113.92 (1F), −127.97 (1F). 79

630.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.21 (s, 1H), 8.26-8.23 (m, 1H),7.30-7.24 (m, 1H), 6.86-6.67(m, 3H), 6.15 (d, J = 16.8 Hz, 1H),5.74-5.69 (m, 1H), 4.81- 4.77 (m, 2H), 4.55- 4.47 (m, 1H), 4.15-4.08 (m,2H), 3.82-3.78 (m, 1H), 3.75 (s, 3H), 1.59-1.54 (m, 2H), 1.29-1.16 (m,6H), 0.92-0.83 (m, 6H), 0.82-0.64 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm):δ −115.06 (1F), −128.21 (1F). 88

686.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.43-8.36 (m, 1H), 7.26-7.19(m, 1H), 6.87-6.76 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.60 (t, J = 8.8Hz, 1H), 6.29 (dd, J = 16.8, 5.6 Hz, 1H), 5.80 (dd, J = 10.8, 2.0 Hz,1H), 5.11-4.99 (m, 1H), 4.53-4.37 (m, 2H), 4.18-4.03 (m, 1H), 3.97- 3.94(m, 4H), 3.89-3.76 (m, 1H), 3.75-3.51 (m, 1H), 3.42-3.31 (m, 1H),3.24-3.14 (m, 4H), 1.66-1.51 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H),1.08-0.98 (m, 2H), 0.97- 0.89 (m, 2H), 0.87-0.78 (m, 2H), 0.77-0.68 (m,2H). FNMR (376 MHz, methanol-d₄, ppm): δ −116.73 (1F). 89

700.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.40-8.39 (m, 1H), 7.26-7.20(m, 1H), 6.83-6.76 (m, 1H), 6.67-6.59 (m, 2H), 6.31-6.27 (m, 1H),5.82-5.79 (m, 1H), 5.11- 4.99 (m, 1H), 4.95-4.71 (m, 1H), 4.53-4.38 (m,2H), 4.18-4.04 (m, 1H), 3.83-3.46 (m, 5H), 3.19-3.03 (m, 5H), 2.88 (s,3H), 1.62-1.52 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H), 1.05-0.92 (m, 4H),0.85-0.72 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −116.78 (1F). 116

670.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.43-8.36 (m, 1H), 7.52-7.46(m, 1H), 7.35-7.31 (m, 1H), 7.25-7.15 (m, 2H), 6.87-6.76 (m, 1H), 6.29(dd, J = 16.8, 4.8 Hz, 1H), 5.81 (dd, J = 10.4, 2.0 Hz, 1H), 5.11-4.99(m, 1H), 4.53-4.37 (m, 2H), 4.18-4.03 (m, 1H), 3.97-3.94 (m, 4H),3.89-3.76 (m, 1H), 3.75-3.51 (m, 1H), 3.42-3.31 (m, 1H), 3.24-3.14 (m,4H), 1.66-1.51 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H). 1.08-1.03 (m, 2H),1.02-0.93 (m, 2H), 0.91-0.81 (m, 2H), 0.80-0.71 (m, 2H). FNMR (376 MHz,methanol-d₄, ppm): δ −114.81 (1F). 93

699.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.47-8.40 (m, 1H), 7.15-7.09(m, 1H), 6.83-6.80 (m, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.39 (t, J = 8.8Hz, 1H), 6.32-6.26 (m, 1H), 5.83-5.79 (m, 1H), 5.06-4.96 (m, 1H),4.53-4.50 (m, 1H), 4.41-4.35 (m, 1H), 4.16-4.06 (m, 1H), 3.94-3.46 (m,5H), 3.20-3.05 (m, 5H), 2.89 (s, 3H), 1.65-1.41 (m, 5H), 1.13-1.01 (m,3H), 0.94-0.71 (m, 5H). FNMR (376 MHz, methanol-d₄, ppm): δ −115.40(1F). 87

703.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.43-8.40 (m, 1H), 7.09 (dd, J= 14.8, 8.0 Hz, 1H), 6.87-6.74 (m, 1H), 6.52 (d, J = 8.0 Hz, 1H),6.36-6.25 (m, 2H), 5.83-5.78 (m, 1H), 5.05-4.86 (m, 1.5H), 4.56-4.24 (m,2H), 4.16- 3.82 (m, 6H), 3.61-3.43 (m, 0.5H), 3.27-3.20 (m, 4H),2.74-2.58 (m, 1H), 2.55-2.40 (m, 1H), 1.52-1.42 (m, 3H), 1.38-1.22 (m,3H), 1.16-1.07 (m, 6H), 1.06-0.88 (m, 6H). FNMR (376 MHz, methanol-d₄,ppm): δ −117.07 (1F). 80

629.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.31-8.27 (m, 1H), 7.15-7.09 (m,1H), 6.87-6.74 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.41-6.36 (m, 1H),6.17-6.13 (m, 1H), 5.74-5.70 (m, 1H), 4.80-4.77 (m, 2H), 4.14- 4.07 (m,1H), 3.82-3.78 (m, 2H), 3.76 (s, 3H), 3.50-3.47 (m, 1H), 1.70-1.60 (m,2H), 1.28-1.13 (m, 6H), 0.95-0.86 (m, 4H), 0.86-0.73 (m, 4H). FNMR (376MHz, DMSO-d₆, ppm): δ −113.81 (1F), −126.79 (1F). 85

684.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.42-8.39 (m, 1H), 7.50-7.47(m, 1H), 7.36-7.32 (m, 1H), 7.26-7.16 (m, 2H), 6.81-6.74 (m, 1H),6.30-6.24 (m, 1H), 5.83- 5.78 (m, 1H), 5.00-4.84 (m, 2H), 4.52-4.28 (m,2H), 3.98-3.88 (m, 5.5H), 3.54-3.46 (m, 0.5H), 3.29-3.19 (m, 4H),1.62-1.50 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H), 1.35- 1.25 (m, 3H),1.07-0.98 (m, 4H), 0.88-0.76 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm):δ −114.71 (1F). 86

700.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.40 (d, J = 5.6 Hz, 1H),7.25-7.20 (m, 1H), 6.87-6.74 (m, 1H), 6.68-6.59 (m, 2H), 6.30-6.24 (m,1H), 5.82-5.78 (m, 1H), 4.99-4.87 (m, 2H), 4.51-4.27 (m, 2H), 3.96-3.89(m, 5.5H), 3.54-3.51 (m, 0.5H), 3.21-3.18 (m, 4H), 1.58-1.52 (m, 2H),1.47 (d, J = 6.8 Hz, 3H), 1.36-1.26 (m, 3H), 1.05-0.93 (m, 4H),0.83-0.71 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −116.71 (1F). 91

684.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.43-8.38 (m, 1H), 7.50-7.48(m, 1H), 7.34-7.31 (m, 1H), 7.26-7.16 (m, 2H), 6.83-6.77 (m, 1H),6.31-6.26 (m, 1H), 5.81 (dd, J = 10.4, 2.4 Hz, 1H), 5.12-5.02 (m, 1H),4.84-4.81 (m, 1H), 4.53-4.39 (m, 2H), 4.19-4.04(m, 1H), 3.88- 3.84 (m,1H), 3.71-3.46 (m, 4H), 3.20-3.01 (m, 5H), 2.89 (s, 3H), 1.67-1.53 (m,2H), 1.46 (d, J = 6.0 Hz, 3H), 1.08-0.74 (m, 8H). FNMR (376 MHz,methanol- d₄, ppm): δ −114.87 (1F). 92

685.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.47-8.39 (m, 1H), 7.12 (dd, J= 14.8, 8.4 Hz, 1H), 6.87-6.75 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.39(t, J = 9.2 Hz, 1H), 6.29 (dd, J = 16.4, 5.2 Hz, 1H), 5.81 (dd, J =10.4, 1.6 Hz, 1H), 5.23-4.93 (m, 1H), 4.60-4.30 (m, 2H), 4.25-3.86 (m,6H), 3.81-3.37 (m, 2H), 3.26-3.02 (m, 4H), 1.71- 1.37 (m, 5H), 1.13-1.00(m, 3H), 0.99-0.81 (m, 3H), 0.79-0.65 (m, 2H). FNMR (376 MHz,methanol-d₄, ppm): δ −115.33 (1F). 94

672.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.26-8.22 (m, 1H), 7.52-7.50(m, 1H), 7.36-7.32 (m, 1H), 7.26-7.18 (m, 2H), 6.88-6.74 (m, 1H),6.30-6.24 (m, 1H), 5.83- 5.78 (m, 1H), 5.03-5.01 (m, 1H), 4.91-4.88 (m,0.5H), 4.52-4.40 (m, 1H), 4.34-4.28 (m, 1H), 4.14-4.12 (m, 4H),4.00-3.90 (m, 2H), 3.56-3.52 (m, 0.5H), 3.31-3.28 (m, 4H), 2.61-2.55 (m,2H), 1.46 (d, J = 6.8 Hz, 3H), 1.35-1.25 (m, 3H), 1.13 (dd, J = 6.4 Hz,2.4 Hz, 6H), 0.97-0.94 (m, 6H). FNMR (376 MHz, methanol-d₄, ppm): δ−115.39 (1F), −128.98 (1F). 95

688.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.21-8.18 (m, 1H), 7.27-7.21(m, 1H), 6.87-6.74 (m, 1H), 6.67-6.59 (m, 2H), 6.30-6.24 (m, 1H),5.82-5.78 (m, 1H), 5.02- 5.01 (m, 1H), 4.90-4.89 (m, 0.5H), 4.51-4.39(m, 1H), 4.34-4.27 (m, 1H), 4.12-4.10 (m, 4H), 3.96-3.89 (m, 2H),3.57-3.53 (m, 0.5H), 3.27-3.20 (m, 4H), 2.58-2.53 (m, 2H), 1.45 (d, J =6.4 Hz, 3H), 1.35-1.25 (m, 3H), 1.13-1.10 (m, 6H), 0.97-0.95 (m, 6H).FNMR (376 MHz, methanol-d₄, ppm): δ −116.75 (1F), −128.43 (1F). 96

687.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.24-8.20 (m, 1H), 7.13-7.09(m, 1H), 6.88-6.74 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.40-6.36 (m, 1H),6.31-6.24 (m, 1H), 5.83-5.78 (m, 1H), 5.02-5.00 (m, 1H), 4.90-4.89 (m,0.5H), 4.52-4.40 (m, 1H), 4.34-4.28 (m, 1H), 4.14-4.12 (m, 4H),4.00-3.89 (m, 2H), 3.56-3.51 (m, 0.5H), 3.29- 3.28 (m, 4H), 2.60-2.56(m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.36-1.26 (m, 3H), 1.13-1.11 (m, 6H),0.98-0.95 (m, 6H). FNMR (376 MHz, methanol-d₄, ppm): δ −115.67 (1F),−126.72 (1F). 97

701.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.23-8.20 (m, 1H), 7.14-7.09(m, 1H), 6.81-6.74 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.37 (t, J = 8.4Hz, 1H), 6.31-6.24 (m, 1H), 5.81-5.78 (m, 1H), 5.05-5.01 (m, 2H),4.51-4.28 (m, 2H), 4.00-3.85 (m, 2H), 3.58-3.55 (m, 4H), 3.16-3.10 (m,2H), 2.93 (s, 3H), 2.62-2.53 (m, 2H), 1.46 (d, J = 6.8 Hz. 3H), 1.35 (d,J = 6.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 1H), 1.23 (d, J = 3.6 Hz, 1H),1.13-1.11 (m, 6H), 0.98-0.95 (m, 6H). FNMR (376 MHz, methanol-d₄, ppm):δ −115.82 (1F), −126.89 (1F). 98

683.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.23-8.19 (m, 1H), 7.16-7.11(m, 1H), 6.87-6.74 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.43-6.39 (m, 1H),6.30-6.24 (m, 1H), 5.82-5.78 (m, 1H), 5.01-5.00 (m, 1H), 4.96-4.79 (m,1H), 4.52-4.28 (m, 2H), 4.00-3.88 (m, 5.5H), 3.54-3.50 (m, 0.5H),3.23-3.21 (m, 4H), 1.63-1.52 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H),1.36-1.26 (m, 3H), 1.07-1.01 (m, 4H), 0.89-0.74 (m, 4H). FNMR (376 MHz,methanol- d₄, ppm): δ −115.00 (1F), −126.22 (1F). 100

684.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.22-8.18 (m, 1H), 7.30-7.24(m, 1H), 6.85-6.62 (m, 3H), 6.30-6.24 (m, 1H), 5.82-5.78 (m, 1H),5.00-4.84 (m, 2H), 4.52- 4.27 (m, 2H), 3.99-3.89 (m, 5.5H), 3.55-3.51(m, 0.5H), 3.22-3.19 (m, 4H), 1.57-1.52 (m, 2H), 1.46 (d, J = 6.8 Hz,3H), 1.36-1.25 (m, 3H), 1.06-0.95 (m, 4H), 0.83- 0.72 (m, 4H). FNMR (376MHz, methanol-d₄, ppm): δ −115.46 (1F), −127.64 (1F). 102

668.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.23-8.19 (m, 1H), 7.53-7.45(m, 2H), 7.27-7.19 (m, 2H), 6.83-6.74 (m, 1H), 6.30-6.28 (m, 1H),5.81-5.78 (m, 1H), 5.02- 4.89 (m, 2H), 4.51-4.28 (m, 2H), 4.00-3.89 (m,5.5H), 3.55-3.50 (m, 0.5H), 3.23-3.20 (m, 4H), 1.62-1.53 (m, 2H), 1.45(d, 7= 6.8 Hz, 3H), 1.35-1.25 (m, 3H), 1.08- 0.99 (m, 4H), 0.87-0.73 (m,4H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.82, −128.93 (1F). 118

657.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.32-8.27 (m, 1H), 7.13-7.10(m, 1H), 6.84-6.78 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.39-6.37 (m, 1H),6.35-6.27 (m, 1H), 5.82 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.11 (s, 1H),4.54-4.40 (m, 2H), 4.21-4.06 (m, 1H), 3.87-3.75 (m, 1H), 3.74- 3.55 (m,1H), 3.38-2.32 (m, 1H), 2.87-2.82 (m, 2H), 1.49-1.47 (m, 3H), 1.19 (dd,J = 6.4 Hz, 2.4 Hz, 6H), 1.03 (dd, J = 6.0 Hz, 2.4 Hz, 6H). 105

629.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.32-8.22 (m, 1H), 7.14-7.08(m, 1H), 6.84-6.81 (m, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.40-6.35 (m, 1H),6.29 (dd, J = 16.0, 4.0 Hz, 1H), 5.81 (dd, J = 10.4, 1.6 Hz, 1H), 5.06(s, 1H), 4.50-4.43 (m, 2 H), 4.20-4.05 (m, 1H), 3.84-3.75 (m, 1H),3.74-3.55 (m, 1H), 3.36-3.30 (m, 1H), 2.72-2.66 (m, 2H), 2.30-2.25 (m,1H), 1.45 (d, J = 5.6 Hz, 3H), 1.23-1.14 (m, 8H), 1.09-1.06 (m, 2H),0.99-0.98 (m, 6H). 109

619.5 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.20 (s, 1H), 8.30-8.27 (m, 1H),7.32-7.26 (m, 1H), 6.90-6.86 (m, 1H), 6.83-6.69 (m, 2H), 6.50 (s, 2H),6.21 (dd, J = 14.4, 2.4 Hz, 1H), 5.78-5.73 (m, 1H), 4.90-4.75 (m, 2H),4.55-4.45 (m, 0.5H), 4.17-4.12 (m, 1H), 3.90-3.75 (m, 2H), 3.55-3.45 (m,0.5H), 2.44-2.40 (m, 2H), 1.35-1.15 (m, 6H), 1.00 (d, J = 6.8 Hz, 6H),0.86 (d, J = 6.8 Hz, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ −115.72,−129.06 (1F). 115

699.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.46-8.38 (m, 1H), 7.11-7.09(m, 1H), 6.86-6.73 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.42-6.38 (m, 1H),6.30-6.25 (m, 1H), 5.82-5.78 (m, 1H), 5.07-4.84 (m, 2H), 4.60-4.19 (m,2H), 4.09-4.80 (m, 6H), 3.22-3.19 (m, 4H), 1.57-1.52 (m, 2H), 1.51-1.40(m, 3H), 1.34-1.21 (m, 3H), 1.06- 0.92 (m, 4H), 0.90-0.72 (m, 4H). FNMR(376 MHz, methanol-d₄, ppm): δ −115.20 (1F). 99

697.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.23-8.20 (m, 1H), 7.17-7.11(m, 1H), 6.81-6.74 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.43-6.39 (m, 1H),6.30-6.25 (m, 1H), 5.83-5.78 (m, 1H), 5.01-4.89 (m, 2H), 4.42-4.28 (m,2H), 3.96-3.89 (m, 2H), 3.54-3.46 (m, 2H), 3.40-3.06 (m, 6H), 2.91 (s,3H), 1.64-1.54 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H), 1.36-1.26 (m, 3H),1.05-1.04 (m, 4H), 0.89-0.78 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm):δ −115.06 (1F), −126.25 (1F). 101

698.4 HNMR (400 MHz, methanol-d₄, ppm): δ 8.22-8.18 (m, 1H), 7.30-7.24(m, 1H), 6.80-6.70 (m, 1H), 6.68-6.62 (m, 2H), 6.30-6.24 (m, 1H),5.82-5.78 (m, 1H), 5.00- 4.89 (m, 2H), 4.52-4.27 (m, 2H), 3.98-3.89 (m,2H), 3.55-3.48 (m, 2H), 3.40-3.07 (m, 6H), 2.89 (s, 3H), 1.61-1.52 (m,2H), 1.46 (d, J = 6.4 Hz, 3H), 1.36-1.25 (m, 3H), 1.05-0.97 (m, 4H),0.84-0.73 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −115.57 (1F),−127.69 (1F). 103

682. HNMR (400 MHz, methanol-d₄, ppm): δ 8.24-8.20 (m, 1H), 7.53-7.44(m, 2H), 7.27-7.19 (m, 2H), 6.81-6.74 (m, 1H), 6.30-6.27 (m, 1H),5.81-5.78 (m, 1H), 5.02- 4.89 (m, 2H), 4.51-4.28 (m, 2H), 4.00-3.89 (m,2H), 3.54-3.46 (m, 2H), 3.40-3.08 (m, 6H), 2.90 (s, 3H), 1.62-1.54 (m,2H), 1.46 (d, J = 6.8 Hz, 3H), 1.35-1.25 (m, 3H), 1.08-0.99 (m, 4H),0.89-0.74 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −114.87 (1F),−128.95 (1F). 81

591.2 HNMR (400 MHz, CDCl₃, ppm): δ 9.62 (s, 1H), 7.92 (dd, J = 9.4, 4.6Hz, 1H), 7.39-7.29 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.70-6.56 (m, 3H),6.44 (dd, J = 16.6, 1.9 Hz, 1H), 5.84 (dd, J = 10.4, 1.9 Hz, 1H),5.31-5.01 (m, 1H), 4.95-4.65 (m, 1H), 4.61-4.25 (m, 1H), 4.35-4.03 (m,1H), 3.96 (s, 3H), 3.81-3.48 (m, 2H), 3.38-2.95 (m, 1H), 2.81-2.59 (m,1H), 2.02 (d, J = 7.7 Hz, 3H), 1.54 (t, J = 27.5 Hz, 3H), 1.26 (dd, J =6.9, 4.0 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H). FNMR (376 MHz, CDCl₃, ppm):δ −107.71 (1F), −121.95 (1F). 106

621.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.13 (s, 1H), 8.42-8.38 (m, 1H),7.31-7.21 (m, 1H), 6.88-6.81 (m, 1H), 6.74-6.71 (m, 1H), 6.68-6.66 (m,2H), 6.21 (dd, J = 16.8, 6.8 Hz, 1H), 5.77 (dd, J = 10.4, 2.4 Hz, 1H),4.95 (brs, 1H), 4.41-4.27 (m, 2H), 4.16-4.13 (m, 2H), 3.68- 3.63 (m,1H), 3.50-3.46 (m, 1H), 3.27-3.24 (m, 1H), 3.12-3.11 (m, 1H), 2.60-2.40(m, 2H), 1.33 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 6H), 0.96-0.82(m, 6H). FNMR (376 MHz, DMSO-d₆, ppm): δ −115.38 (1F). 107

635.4 HNMR (300 MHz, DMSO-d₆, ppm): δ 10.11 (s, 1H), 8.43 (s, 1H),7.30-7.22 (m, 1H), 6.87-6.81 (m, 1H), 6.77-6.66 (m, 2H), 6.51 (s, 2H),6.21 (dd, J = 16.5, 2.4 Hz, 1H), 5.78-5.73 (m, 1H), 4.84-4.48 (m, 2H),4.22- 4.02 (m, 1.5H), 3.95-3.78 (m, 2H), 3.55-3.45 (m, 0.5H), 2.46-2.40(m, 2H), 1.31 (t, J = 6.3 Hz, 3H), 1.29-1.24 (m, 3H), 1.00 (d, J = 6.6,6H), 0.86 (d, J = 6.6 Hz, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ −115.86(1F). 110

617.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.13 (s, 1H), 8.37 (s, 1H),7.32-7.22 (m, 1H), 6.95-6.80 (m, 1H), 6.78-6.65 (m, 2H), 6.26-6.19 (m,3H), 5.77 (dd, J = 10.4, 2.4 Hz, 1H), 4.94-4.86 (m, 1H), 4.42-3.99 (m,3H), 3.75-3.69 (m, 1H), 3.65-3.61 (m, 1H), 3.11-3.06 (m, 1H), 1.58-1.40(m, 2H), 1.33 (s, 3H), 0.90-0.80 (m, 2H), 0.78-0.70 (m, 4H), 0.64-0.60(m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ −115.34 (1F). 111

631.2 HNMR (300 MHz, DMSO-d₆, ppm): δ 10.18 (s, 1H), 8.40 (s, 1H),7.32-7.24 (m, 1H), 6.85-6.72 (m, 3H), 6.28 (s, 1H), 6.21-6.16 (m, 2H),5.77-5.73 (m, 1H), 4.80-4.48 (m, 2H), 4.30-3.99 (m, 1.5H), 3.92-3.75 (m,2H), 3.55- 3.45 (m, 0.5H), 1.44-1.20 (m, 8H), 0.86-0.73 (m, 8H). FNMR(282 MHz, DMSO-d₆, ppm): δ −115.34 (1F). 10

648. HNMR (300 MHz, DMSO-d₆, ppm): δ 8.49 (s, 1H), 7.52-7.48 (m, 1H),7.34-7.25 (m, 2H), 7.19-7.15 (m, 1H), 6.95-6.78 (m, 1H), 6.22 (d, J =16.7 Hz, 1H), 5.78 (d, J = 10.4 Hz, 1H), 5.00 (brs, 1H), 4.93 (s, 1H),4.50- 3.94 (m, 3H), 3.91-3.56 (m, 2H), 3.14-3.10 (m, 1H), 2.82-2.64 (m,2H), 1.50 (s, 6H), 1.35 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.6 Hz, 6H),0.95 (d, J = 6.6 Hz, 6H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.39 (1F).135

602.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.71 (s, 1H), 8.27-8.19 (m,1H), 7.54-7.47 (m, 1H), 7.43-7.38 (m, 1H), 7.25-7.17 (m, 2H), 5.36-5.18(m, 2H), 5.11-4.98 (m, 1H), 4.81-4.72 (m, 0.5H), 4.51-4.23 (m, 2H),3.99- 3.80 (m, 2H), 3.56-3.52 (m, 0.5H), 1.82-1.64 (m, 2H), 1.48 (d, J =6.4 Hz, 3H), 1.43-1.28 (m, 3H), 1.18-1.03 (m, 4H), 1.01-0.81 (m, 4H).FNMR (376 MHz, methanol-d₄, ppm): δ −106.11(0.5F), −106.96 (0.5F),−114.72 (1F), −128.35 (1F). 108

605.4 HNMR (300 MHz, DMSO-d₆, ppm): δ 10.22 (s, 1H), 8.30-8.24 (m, 1H),7.32-7.25 (m, 1H), 7.00-6.60 (m, 4H), 6.23 (d, J = 8.7 Hz, 1H), 5.75 (d,J = 16.5 Hz, 1H), 4.91 (brs, 1H), 4.42-4.38 (m, 1H), 4.31-4.27 (m, 2H),3.71-3.58 (m, 2H), 3.28-3.07 (m, 1H), 2.36-2.27 (m, 2H), 1.33 (d, J =6.3 Hz, 3H), 1.02 (d, J = 6.0 Hz, 6H), 0.86 (d, J = 6.6 Hz, 6H). FNMR(282 MHz, DMSO-d₆, ppm): δ −115.76 (1F), −128.27 (1F). 112

601.5 HNMR (300 MHz, DMSO-d₆, ppm): δ 10.22 (s, 1H), 8.26-8.20 (m, 1H),7.32-7.30 (m, 1H), 6.89-6.70 (m, 3H), 6.26-6.17 (m, 3H), 5.77 (d, J =10.4 Hz, 1H), 4.89 (brs, 1H), 4.45-4.02 (m, 3H), 3.69-3.61 (m, 2H),3.22- 3.08 (m, 1H), 1.52-1.39 (m, 2H), 1.33 (d, J = 6.0 Hz, 3H),0.90-0.55 (m, 8H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.87 (1F), −128.82(1F). 113

615.3 HNMR (300 MHz, DMSO-d₆, ppm): δ 10.25 (s, 1H), 8.35-8.21 (m, 1H),7.40-7.25 (m, 1H), 6.88-6.68 (m, 4H), 6.19 (dd, J = 16.8, 2.4 Hz, 1H),5.76 (dt, J = 10.5, 3.0 Hz, 1H), 4.81 (brs, 2H), 4.55-3.70 (m, 3.5H),3.55- 3.45 (m, 0.5H), 1.48 (s, 2H), 1.37-1.11 (m, 6H), 0.96- 0.56 (m,8H). FNMR (282 MHz, DMSO-d₆, ppm): δ −115.21 (1F), −128.21 (1F). 128

600.2 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.73 (s, 1H), 8.46 (d, J = 4.2 Hz,1H), 7.57-7.53 (m, 1H), 7.38-7.30 (m, 3H), 6.87-6.78 (m, 1H), 6.20 (d, J= 16.8 Hz, 1H), 5.76 (d, J = 10.3 Hz, 1H), 4.95-4.77 (m, 1.5H), 4.55-4.45 (m, 0.5H), 4.27-4.16 (m, 1.5H), 3.93-3.81 (m, 2H), 3.51-3.47 (m,0.5H), 1.85-1.65 (m, 2H), 1.35 (dd, J = 6.4, 2.8 Hz, 3H), 1.24 (dd, J =19.5, 6.6 Hz, 3H), 1.08- 0.74 (m, 8H). FNMR (282 MHz, DMSO-d₆, ppm): δ−112.94 (1F). 133

617.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.73 (s, 1H), 8.27-8.19 (m,1H), 7.15-7.09 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.42-6.36 (m, 1H),5.35-5.19 (m, 2H), 5.11- 4.97 (m, 1H), 4.81-4.72 (m, 0.5H), 4.51-4.23(m, 2H), 3.99-3.78 (m, 2H), 3.56-3.51 (m, 0.5H), 1.85-1.64 (m, 2H), 1.48(d, J = 6.8 Hz, 3H), 1.43-1.28 (m, 3H), 1.15- 1.05 (m, 4H), 1.02-0.95(m, 2H), 0.87-0.79 (m, 2H). FNMR (376 MHz, methanol-d₄, ppm): δ −106.08(0.5F), −107.03 (0.5F), -114.93 (1F), −125.60 (1F). 134

618.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.69 (s, 1H), 8.24-8.17 (m,1H), 7.28-7.21 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 8.8 Hz,1H), 5.35-5.19 (m, 2H), 5.11-4.97 (m, 1H), 4.81-4.72 (m, 0.5H),4.51-4.23 (m, 2H), 3.99-3.80 (m, 2H), 3.58-3.52 (m, 0.5H), 1.82-1.64 (m,2H), 1.48 (d, J = 6.4 Hz, 3H), 1.43-1.28 (m, 3H), 1.16-0.99 (m, 4H),0.98-0.79 (m, 4H). FNMR (376 MHz, methanol-d₄, ppm): δ −106.09 (0.5F),−106.94 (0.5F), −116.11 (1F), −127.30 (1F). 136

603.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.73 (s, 1H), 8.25 (d, J = 9.2Hz, 1H), 7.15-7.09 (m, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.42-6.37 (m, 1H),5.33 (dd, J = 21.2, 4.0 Hz, 1H), 5.25 (dd, J = 10.8, 4.0 Hz, 1H),5.11-5.03 (m, 1H), 4.51-3.92 (m, 3H), 3.91-3.33 (m, 3H), 1.82-1.72 (m,2H), 1.49 (d, J = 6.8 Hz, 3H), 1.18-1.05 (m, 4H), 1.02-0.80 (m, 4H).FNMR (376 MHz, methanol-d₄, ppm): δ −106.88 (1F), −115.04 (1F), −125.77(1F). 137

604.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.69 (s, 1H), 8.22 (d, J = 9.2Hz, 1H), 7.27-7.20 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.63-6.58 (m, 1H),5.33 (dd, J = 21.2, 4.0 Hz, 1H), 5.25 (dd, J = 10.8, 4.0 Hz, 1H),5.11-5.03 (m, 1H), 4.51-3.92 (m, 3H), 3.91-3.33 (m, 3H), 1.79-1.69 (m,2H), 1.49 (d, J = 6.8 Hz, 3H), 1.15-1.00 (m, 4H), 0.99-0.79 (m, 4H).FNMR (376 MHz, methanol-d₄, ppm): δ −106.84 (1F), −116.16 (1F), −127.44(1F). 138

588.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.71 (s, 1H), 8.25 (d, J = 9.2Hz, 1H), 7.53-7.47 (m, 1H), 7.42-7.37 (m, 1H), 7.25-7.16 (m, 2H), 5.33(dd, J = 21.6, 4.0 Hz, 1H), 5.25 (dd, J = 10.4, 4.0 Hz, 1H), 5.11-5.03(m, 1H), 4.51-3.92 (m, 3H), 3.91-3.33 (m, 3H), 1.79-1.71 (m, 2H), 1.49(d, J = 6.8 Hz, 3H), 1.18-1.03 (m, 4H), 1.01- 0.81 (m, 4H). FNMR (376MHz, methanol-d₄, ppm): δ −106.87 (1F), −114.83 (1F), −128.55 (1F). 125

602.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.15 (s, 1H), 8.70 (s, 1H), 8.43(brs, 1H), 7.27-7.25 (m, 1H), 6.91- 6.82 (m, 1H), 6.75-6.67 (m, 2H),6.23-6.19 (m, 1H), 5.78 (dd, J = 10.4, 2.4 Hz, 1H), 4.99-4.93 (m, 1H),4.42- 4.28 (m, 2H), 4.18-4.03 (m, 1H), 3.81-3.62 (m, 2H), 3.18-3.02 (m,1H), 1.77-1.72 (m, 2H), 1.41-1.30 (m, 3H), 1.03-0.73 (m, 8H). FNMR (376MHz, DMSO-d₆, ppm): δ −115.40 (1F). 130

634.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.16 (s, 1H), 8.71 (s, 1H),8.51-8.30 (m, 1H), 7.32-7.20 (m, 1H), 6.79-6.64 (m, 2H), 5.42-5.16 (m,2H), 5.01-4.80 (m, 1H), 4.85-4.72 (m, 0.5H), 4.35-4.12 (m, 2H),3.92-3.42 (m, 2.5H), 1.78-1.60 (m, 2H), 137-1.28 (m, 6H), 0.97- 0.80 (m,8H). FNMR (376 MHz, DMSO-d₆, ppm): δ −105.08 (1F), −115.35 (1F). 67

614.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.48-8.46 (m, 1H), 8.11 (s, 1H),7.51-7.42 (m, 1H), 7.36 (s, 1H), 7.31- 7.13 (m, 3H), 6.88 (q, J = 14.8,14.0 Hz, 1H), 6.22 (d, J = 16.5 Hz, 1H), 5.78 (dd, J = 10.4, 2.4 Hz,1H), 4.93 (brs, 1H), 4.44-4.30 (m, 2H), 4.11 (dd, J = 49.1, 13.3 Hz,1H), 3.83 (s, 3H), 3.79-3.61 (m, 2H), 3.13-3.09 (m, 1H), 2.65-2.50 (m,1H), 2.18-2.09 (m, 3H), 1.35-1.30 (m, 3H), 1.20-1.10 (m, 3H), 1.09-0.99(m, 3H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.49 (1F). 129

620.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.16 (s, 1H), 8.70 (s, 1H),8.48-8.39 (m, 1H), 7.57-7.49 (m, 1H), 7.29-7.23 (m, 1H), 6.75-6.67 (m,2H), 5.38 (dd, J = 18.4, 4.0 Hz, 1H), 5.01-5.00 (m, 1H), 4.34-4.02 (m,3H), 3.86-3.30 (m, 3H), 1.77-1.66 (m, 2H), 1.42-1.32 (m, 3H), 0.98-0.80(m, 8H). FNMR (376 MHz, DMSO- d₆, ppm): δ −104.95 (1F), −115.42 (1F).131

619.2 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.74 (s, 1H), 8.51-8.40 (m, 1H),7.15-7.05 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.39 (t, J = 9.0 Hz, 1H),5.45-5.22 (m, 3H), 5.05-4.95 (m, 1H), 4.37-4.26 (m, 2H), 4.10-3.96 (m,1H), 3.78-3.64 (m, 1H), 3.60-3.10 (m, 2H), 1.91-1.73 (m, 2H), 1.38 (dd,J = 25.2, 6.6 Hz, 3H), 1.13-0.69 (m, 8H). FNMR (282 MHz, DMSO-d₆, ppm):δ −104.95 (1F), −114.15 (1F). 120

688.5 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.74 (s, 1H), 8.50-8.40 (m, 1H),7.23-7.01 (m, 1H), 6.61 (d, J = 3.4 Hz, 2H), 6.51 (d, J = 8.3 Hz, 1H),6.38 (t, J = 9.4 Hz, 1H), 5.33-4.81 (m, 4H), 4.48-3.86 (m, 5H)),3.69-3.61 (m, 3H), 3.22-3.14 (m, 2H), 1.92-1.71 (m, 2H), 1.44- 1.26 (m,3H), 1.10-0.75 (m, 8H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.15 (1F),−177.44 (1F). 121

632.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.31-8.25 (m, 1H), 7.51-7.45(m, 1H), 7.31-7.26 (m, 1H), 7.23-7.15 (m, 2H), 6.88-6.74 (m, 1H),6.31-6.25 (m, 1H), 5.83- 5.78 (m, 1H), 5.12-5.00 (m, 1H), 4.96-4.87 (m,0.5H), 4.60-4.46 (m, 1H), 4.40-4.30 (m, 1H), 4.05-3.85 (m, 2H),3.58-3.50 (m, 0.5H), 2.90-2.74 (m, 2H), 1.48 (d, J = 6.4 Hz, 3H),1.38-1.27 (m, 3H), 1.26-1.20 (m, 6H), 1.07-1.02 (m, 6H). FNMR (376 MHz,methanol-d₄, ppm): δ −115.25 (1F), −128.10 (1F). 122

648.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.26-8.21 (m, 1H), 7.21 (dd, J= 14.8, 8.0 Hz, 1H), 6.88-6.74 (m, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.58(t, J = 8.8 Hz, 1H), 6.31- 6.24 (m, 1H), 5.83-5.78 (m, 1H), 5.12-5.00(m, 1H), 4.96-4.87 (m, 0.5H), 4.60-4.45 (m, 1H), 4.43-4.27 (m, 1H),4.05-3.85 (m, 2H), 3.61-3.52 (m, 0.5H), 2.87-2.71 (m, 2H), 1.48 (d, J =6.4 Hz, 3H), 1.38-1.27 (m, 3H), 1.22-1.19 (m, 6H), 1.07-1.03 (m, 6H).FNMR (376 MHz, methanol-d₄, ppm): δ −117.11 (1F). −127.79 (1F). 123

647.3 HNMR (400 MHz, methanol-d₄, ppm): δ 8.29-8.23 (m, 1H), 7.09 (dd, J= 14.4, 8.0 Hz, 1H), 6.88-6.74 (m, 1H), 6.47 (d, J = 8.4 Hz, 1H),6.38-6.33 (m, 1H), 6.31-6.24 (m, 1H), 5.83-5.78 (m, 1H), 5.12-5.00 (m,1H), 4.96- 4.87 (m, 0.5H), 4.60-4.45 (m, 1H), 4.42-4.27 (m, 1H),4.05-3.85 (m, 2H), 3.56-3.47 (m, 0.5H), 2.90-2.74 (m, 2H), 1.48 (d, J =6.4 Hz, 3H), 1.38-1.27 (m, 3H), 1.23- 1.17 (m, 6H), 1.08-1.05 (m, 6H).FNMR (376 MHz, methanol-d₄, ppm): δ −115.73 (1F). −125.89 (1F). 119

651.2 HNMR (400 MHz, methanol-d₄, ppm): δ 8.28-8.23 (m, 1H), 7.43 (t, J= 72.4 Hz, 1H), 7.16-7.11 (m, 1H), 6.85- 6.77 (m, 1H), 6.55 (d, J = 8.4Hz, 1H), 6.43-6.39 (m, 1H), 6.32-6.27 (m, 1H), 5.81 (dd, J = 10.4, 2.4Hz, 1H), 5.13-5.03 (m, 1H), 4.54-4.40 (m, 2H), 4.20-4.05 (m, 1H),3.84-3.55(m, 2H), 3.34-3.22 (m, 1H), 1.81-1.69 (m, 2H), 1.47-1.46 (m,3H), 1.15-1.12 (m, 4H), 1.10- 0.89 (m, 4H). FNMR (376 MHz, methanol-d₄,ppm): δ −91.15 (2F), −115.14 (1F), −125.91 (1F). 132

633.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.75 (s, 1H), 8.55-8.40 (m, 1H),7.15-7.05 (m, 1H), 6.51 (d, J = 8.0 Hz, 1H), 6.38 (t, J = 9.2 Hz, 1H),5.41-5.30 (m, 1H), 5.23-5.20 (m, 2H), 5.01-4.62 (m, 1.5H), 4.40-4.30 (m,1H), 4.14-4.07 (m, 1H), 4.04-3.82 (m, 1H), 3.84-3.40 (m, 1.5H),1.87-1.63 (m, 2H), 1.48-1.17 (m, 6H), 0.96- 0.92 (m, 6H), 0.88-0.78 (m,2H). FNMR (376 MHz, DMSO-d₆, ppm): δ −104.54 (1F), −114.23 (1F). 140

659.4 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.74 (s, 1H), 8.57-8.34 (m, 1H),7.11 (q, J = 8.1 Hz, 1H), 6.81-6.56 (m, 2H), 6.51 (d, J = 8.2 Hz, 1H),6.38 (t, 1H), 5.25- 5.15 (m, 2H), 4.92-4.47 (m, 2H), 4.40-3.69 (m, 6H),3.63-3.30 (m, 3H), 1.86-1.67 (m, 2H), 1.42-1.11 (m, 6H), 1.10-0.77 (m,8H). FNMR (282 MHz, DMSO-d₆, ppm): δ −114.15 (1F). 73

599.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.36-8.34 (m, 2H), 7.54-7.49 (m,1H), 7.34-7.21 (m, 3H), 6.94-6.84 (m, 1H), 6.24-6.19 (m, 1H), 5.78 (dd,J = 10.4, 2 Hz, 1H), 4.94 (brs, 1H), 4.45-4.30 (m, 2H), 4.19-4.03 (m,1H), 3.83 (s, 3H), 3.94-3.63 (m, 2H), 3.55-3.10 (m, 1H), 2.80-2.76 (m,1H), 2.20-2.10 (m, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.20-1.10 (m, 3H),1.08-0.99 (m, 3H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.34 (1F), −129.70(1F). 139

645.5 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.79-8.72 (m, 1H), 8.55-8.37 (m,1H), 7.15-7.05 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.38 (t, J = 9.0 Hz,1H), 5.30-4.65 (m, 3H), 4.51-4.03 (m, 4H), 3.90-3.35 (m, 6H), 1.82-1.72(m, 2H), 1.39-1.14 (m, 6H), 1.09-0.75 (m, 8H). FNMR (376 MHz, DMSO-d₆,ppm): δ −114.00 (1F). 141

614.1 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.50-8.40 (m, 1H), 8.08 (s, 1H),7.52-7.42 (m, 1H), 7.34-7.12 (m, 4H), 6.98-6.80 (m, 1H), 6.28-6.14 (m,1H), 5.78 (dd, J = 10.2, 2.4 Hz, 1H), 4.93 (brs, 1H), 4.48-3.99 (m, 1H),3.78 (s, 3H), 3.72-3.43 (m, 2H), 3.10 (t, J = 11.4 Hz, 1H), 2.85-2.69(m, 1H), 1.98 (s, 3H), 1.42-1.18 (m, 9H). FNMR (282 MHz, DMSO-d₆, ppm) δ−114.53 (1F). 142

614.1 HNMR (300 MHz, DMSO-d₆, ppm): δ 8.50-8.40 (m, 1H), 8.08 (s, 1H),7.52-7.42 (m, 1H), 7.34-7.12 (m, 4H), 6.98-6.80 (m, 1H), 6.30-6.13 (m,1H), 5.78 (dd, J = 10.2, 2.4 Hz, 1H), 4.93 (brs, 1H), 4.48-3.99 (m, 1H),3.78 (s, 3H), 3.72-3.43 (m, 2H), 3.10 (t, J = 11.7 Hz, 1H), 2.85-2.69(m, 1H), 1.98 (s, 3H), 1.42-1.18 (m, 9H). FNMR (282 MHz, DMSO-d₆, ppm) δ−114.50 (1F). 143

617.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.36-8.30 (m, 1H), 8.20 (s, 1H),7.43 (d, J = 9.6 Hz, 1H), 7.08 (dd, J = 14.8, 8.0 Hz, 1H), 6.92-6.82 (m,1H), 6.44 (d, J = 8.0 Hz, 1H), 6.36 (t, J = 8.0 Hz, 1H), 6.23-6.19 (m,1H), 5.77 (dd, J = 10.4, 2.4 Hz, 1H), 5.34 (s, 2H), 4.99 (brs, 1H),4.45-4.37 (m, 0.5H), 4.34-4.22 (m, 1.5H), 4.18- 4.10 (m, 0.5H),4.08-4.01 (m, 0.5H), 3.82-3.76 (m, 4H), 3.68-3.62 (m, 0.5H), 3.49-3.42(m, 0.5H), 3.26-3.23 (m, 0.5H), 3.12-3.06 (m, 0.5H), 3.00-2.90 (m, 1H),1.39 (d, J = 6.8 Hz, 3H), 1.32-1.28 (m, 6H). 144

617.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.27 (t, J = 10.8 Hz, 1H), 8.21(s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.11- 7.05 (m, 1H), 6.91-6.82 (m,1H), 6.44 (d, J = 8.0 Hz, 1H), 6.36 (t, J = 8.0 Hz, 1H), 6.23-6.19 (m,1H), 5.77 (dd, J = 10.4, 2.4 Hz, 1H), 5.33 (s, 2H), 4.88 (brs, 1H),4.45-4.27 (m, 2H), 4.18-4.13 (m, 0.5H), 4.18-4.14 (m, 0.5H), 3.82 (s,3H), 3.65-3.62 (m, 1.5H), 3.62-3.50 (m, 0.5H), 3.23-3.18 (m, 0.5H),3.18-3.10 (m, 0.5H), 3.00-2.90 (m, 1H), 1.40-1.35 (m, 6H), 1.29 (d, J =6.8 Hz, 3H). 147

613.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.28-8.23 (m, 1H), 8.10 (s, 1H),7.32 (s, 1H), 7.06 (dd, J = 14.9, 8.2 Hz, 1H), 6.92-6.80 (m, 1H), 6.42(d, J = 7.9 Hz, 1H), 6.38-6.28 (m, 1H), 6.21 (d, J = 17.1 Hz, 1H), 5.76(dd, J = 10.3, 2.4 Hz, 1H), 5.28 (s, 2H), 4.85 (s, 1H), 4.45- 4.38 (m,0.5H), 4.33-4.26 (m, 1.5 H), 4.20-4.12 (m, 0.5H), 4.05-3.99 (m, 0.5H),3.81 (s, 3H), 3.68-3.60 (m, 1.5H), 3.55-3.46 (m, 0.5H), 3.19-3.06 (m,1H), 2.85-2.77 (m, 1H), 1.94 (s, 3H), 1.36 (t, J = 6.5 Hz, 6H), 1.24 (d,J = 6.9 Hz, 3H). 148

613.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.33-8.28 (m, 1H), 8.10 (s, 1H),7.32 (s, 1H), 7.06 (dd, J = 15.2, 8.0 Hz, 1H), 6.90-6.85 (m, 1H), 6.42(d, J = 8.0 Hz, 1H), 6.37-6.32 (m, 1H), 6.27-6.16 (m, 1H), 5.77 (dd, J =10.4, 2.4 Hz, 1H), 5.30 (s, 2H), 4.94 (s, 1H), 4.43-4.41 (m, 0.5H),4.32-4.14 (m, 2H), 4.06-4.03 (m, 0.5H), 3.86-3.64 (m, 4.5H), 3.49-3.44(m, 0.5H), 3.49-3.44 (m, 0.5H), 3.30-3.26 (m, 0.5H), 3.11-3.06 (m,0.5H), 2.87- 2.76 (m, 1H), 1.95 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H), 1.31(d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H). 149

644.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.03 (brs, 1H), 8.42 (s, 1H),8.06 (s, 1H), 7.27 (s, 1H), 7.25-7.10 (m, 1H), 6.85-6.79 (m, 1H),6.75-6.50 (m, 2H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.80-5.69 (m, 1H),4.92-4.73 (m, 1.5H), 4.53-4.42 (m, 0.5H), 4.18-4.03 (m, 1.5H), 3.97-3.84 (m, 2H), 3.77 (s, 3H), 3.53-3.49 (m, 0.5H), 2.83- 2.75 (m, 1H),1.97 (s, 3H), 1.45-1.15 (m, 12H). 150

644.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 9.88 (brs, 1H), 8.43 (s, 1H), 8.06(s, 1H), 7.27 (s, 1H), 7.19 (dd, J = 15.4, 8.2 Hz, 1H), 6.90-6.77 (m,1H), 6.75-6.60 (m, 2H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.78-5.73 (m,1H), 4.91-4.72 (m, 1.5H), 4.55-4.40 (m, 0.5H), 4.23-3.99 (m, 1.5H),3.97-3.84 (m, 2H), 3.76 (s, 3H), 3.60-3.45 (m, 0.5H), 2.81-2.62 (m, 1H),1.95 (s, 3H), 1.43-1.13 (m, 12H). 153

627.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.50-8.30 (m, 2H), 7.42 (s, 1H),7.06 (dd, J = 15.2, 8.0 Hz, 1H), 6.86- 6.79 (m, 1H), 6.42 (d, J = 8.0Hz, 1H), 6.38-6.31 (m, 1H), 6.19 (dd, J = 16.8, 2.4 Hz, 1H), 5.78-5.73(m, 1H), 5.32 (s, 2H), 4.89-4.82 (m, 1H), 4.79-4.74 (m, 0.5H), 4.49-4.44(m, 0.5H), 4.16-4.05 (m, 1.5H), 3.92-3.86 (m, 5H), 3.58-3.54 (m, 0.5H),2.94-2.84 (m, 1H), 1.99 (s, 3H), 1.35-1.11 (m, 12H). 154

627.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.30-8.15 (m, 2H), 7.34 (s, 1H),7.06 (dd, J = 14.9, 8.2 Hz, 1H), 6.90- 6.77 (m, 1H), 6.42 (d, J = 8.2Hz, 1H), 6.37-6.31 (m, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H), 5.78-5.72(m, 1H), 5.28 (s, 2H), 4.86-4.75 (m, 1.5H), 4.53-4.44 (m, 0.5H),4.20-4.07 (m, 1.5H), 3.90-3.75 (m, 5H), 3.56-3.47 (m, 0.5H), 2.81-2.72(m, 1H), 1.97 (s, 3H), 1.37-1.19 (m, 12H). 155

614.6 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.14 (s, 1H), 8.30-8.26 (m, 1H),8.06 (s, 1H), 7.33-7.17 (m, 2H), 6.89-6.85 (m, 1H), 6.69-6.62 (m, 2H),6.23-6.19 (m, 1H), 5.76 (dd, J = 10.4, 2.4 Hz, 1H), 4.92 (s, 1H), 4.44-4.41 (m, 0.5H), 4.28-4.20 (m, 1.5H), 4.16-4.13 (m, 0.5H), 4.04-4.01 (m,0.5H), 3.88-3.65 (m, 4.5H), 3.55- 3.45 (m, 0.5H), 3.28-3.26 (m, 0.5H),3.13-3.09 (m, 0.5H), 2.85-2.70 (m, 1H), 1.94 (s, 3H), 1.35 (d, J = 6.9Hz, 3H), 1.31 (d, J = 6.6 Hz, 3H), 1.23 (d, J = 6.9 Hz, 3H). 156

614.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.15 (s, 1H), 8.25 (t, J = 10.3Hz, 1H), 8.06 (s, 1H), 7.27 (s, 1H), 7.22 (dd, J = 15.5, 8.0 Hz, 1H),6.87 (dd, J = 25.6, 15.4 Hz, 1H), 6.70-6.54 (m, 2H), 6.25-6.16 (m, 1H),5.76 (dd, J = 10.4, 2.2 Hz, 1H), 4.87 (s, 1H), 4.48-4.22 (m, 2H), 4.19-3.97 (m, 1H), 3.77 (s, 3H), 3.72-3.44 (m, 2H), 3.26-3.10 (m, 1H),2.83-2.69 (m, 1H), 1.93 (s, 3H), 1.39-1.21 (m, 9H). 159

628.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.46 (s, 1H), 8.06 (s, 1H),7.50-7.44 (m, 1H), 7.32-7.16 (m, 4H), 6.89-6.79 (m, 1H), 6.19 (dd, J =16.8, 2.4 Hz, 1H), 5.78- 5.73 (m, 1H), 4.92-4.81 (m, 1H), 4.80-4.74 (m,0.5H), 4.49-4.45 (m, 0.5H), 4.20-4.09 (m, 1.5H), 3.95-3.75 (m, 5H),3.52-3.32 (m, 0.5H), 2.85-2.76 (m, 1H), 2.00 (s, 3H), 1.42-1.13 (m,12H). 160

628.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.47 (s, 1H), 8.07 (s, 1H), 7.47(dd, J = 12.8, 5.9 Hz, 1H), 7.31-7.16 (m, 4H), 6.94-6.73 (m, 1H), 6.19(dd, J = 16.7, 2.1 Hz, 1H), 5.75 (dd, J = 7.4, 5.1 Hz, 1H), 4.86 (s,1H), 4.80- 4.41 (m, 1H), 4.18-4.04 (m, 1.5H), 3.97-3.84 (m, 2H), 3.77(s, 3H), 3.57-3.47 (m, 0.5H), 2.76-2.64 (m, 1H), 1.98 (s, 3H), 1.37-1.16(m, 12H). 161

643.1 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.48-8.40 (m, 1H), 8.07 (s, 1H),7.28 (s, 1H), 7.05-6.98 (m, 1H), 6.90- 6.80 (m, 1H), 6.40 (d, J = 8.4Hz, 1H), 6.33-6.25 (m, 1H), 6.20 (d, J = 16.8 Hz, 1H), 5.80-5.72 (m,1H), 5.17- 5.02 (m, 2H), 4.90-4.72 (m, 1.5H), 4.49-4.44 (m, 0.5H),4.16-4.04 (m, 1.5H), 3.99-3.84 (m, 2H), 3.77 (s, 3H), 3.59-3.50 (m,0.5H), 2.93-2.73 (m, 1H), 2.04-1.92 (m, 3H), 1.40-1.00 (m, 12H). 162

643.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.42 (s, 1H), 8.07 (s, 1H), 7.28(s, 1H), 7.05-6.95 (m, 1H), 6.92-6.77 (m, 1H), 6.40 (d, J = 8.2 Hz, 1H),6.29 (t, J = 8.5 Hz, 1H), 6.23-6.13 (m, 1H), 5.83-5.68 (m, 1H),5.15-5.01 (m, 2H), 4.90-4.70 (m, 1.5H), 4.49-4.44 (m, 0.5H), 4.22-3.98(m, 1.5H), 3.98-3.85 (m, 2H), 3.77 (s, 3H), 3.61-3.48 (m, 0.5H),2.91-2.57 (m, 1H), 2.09-1.86 (m, 3H), 1.36-1.13 (m, 12H). 163

615.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.16 (brs, 1H), 8.45-8.25 (m,2H), 7.26-7.20 (m, 1H), 6.92-6.82 (m, 1H), 6.75-6.48 (m, 2H), 6.23-6.19(m, 1H), 5.77 (d, J = 10.7 Hz, 1H), 4.95 (s, 1H), 4.48-4.25 (m, 2H),4.18-3.96 (m, 1H), 3.78 (s, 3H), 3.73-3.64 (m, 2H), 3.15-3.08 (m, 1H),2.85-2.75 (m, 1H), 2.13 (s, 3H), 1.35 (d, J = 6.6 Hz, 6H), 1.24 (d, J =6.3 Hz, 3H). 164

628.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.41-8.25 (m, 2H), 7.07 (dd, J =15.0, 8.2 Hz, 1H), 6.85 (td, J = 16.8, 10.6 Hz, 1H), 6.43 (d, J = 8.4Hz, 1H), 6.37-6.31 (m, 1H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.80-5.70(m, 1H), 5.32 (s, 2H), 4.97-4.75 (m, 1.5H), 4.52-4.45 (m, 0.5H),4.21-4.04 (m, 1.5H), 3.91-3.85 (m, 2H), 3.81 (s, 3H), 3.55-3.50 (m,0.5H), 2.85-2.75 (m, 1H), 2.18 (s, 3H), 1.33-1.16 (m, 12H). 165

628.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.41-8.23 (m, 2H), 7.10-7.04 (m,1H), 6.90-6.79 (m, 1H), 6.43 (d, J = 8.3 Hz, 1H), 6.37-6.31 (m, 1H),6.19 (dd, J = 16.6, 2.3 Hz, 1H), 5.79-5.74 (m, 1H), 5.32 (s, 2H),4.97-4.75 (m, 1.5H), 4.55-4.48 (m, 0.5H), 4.17-4.09 (m, 1.5H), 3.91-3.85 (m, 2H), 3.81 (s, 3H), 3.57-3.52 (m, 0.5H), 2.81- 2.76 (m, 1H),2.18 (s, 3H), 1.37-1.10 (m, 12H). 166

648.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.15-10.05 (m, 1H), 8.44-8.42 (m,1H), 8.17 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.21 (q, J = 8.0 Hz, 1H),6.92-6.77 (m, 1H), 6.64-6.69 (m, 2H), 6.20 (d, J = 16.8 Hz, 1H),5.80-5.71 (m, 1H), 4.72-4.94 (m, 1.5 H), 4.42-4.52 (m, 0.5 H), 4.16 (d,J = 14.8 Hz, 2H), 3.99-3.85 (m, 2H), 3.79 (s, 3H), 2.99-2.75 (m, 1H),1.45-1.10 (m, 12H). FNMR (376 MHz, DMSO-d₆, ppm) δ −115.47(1F),−127.34(1F). 167

629.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.50 (s, 1H), 8.28 (s, 1H),7.52-7.43 (m, 1H), 7.36-7.11 (m, 3H), 6.89-6.79 (m, 1H), 6.20 (dd, J =16.6, 2.3 Hz, 1H), 5.78- 5.72 (m, 1H), 4.96-4.72 (m, 1.5H), 4.53-4.43(m, 0.5H), 4.20-4.13 (m, 1.5H), 3.98-3.84 (m, 2H), 3.78 (s, 3H),3.57-3.49 (m, 0.5H), 2.81-2.65 (m, 1H), 2.17 (s, 3H), 1.50-1.10 (m,12H). 168

629.6 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.48 (s, 1H), 8.28 (s, 1H),7.52-7.44 (m, 1H), 7.32-7.16 (m, 3H), 6.89-6.78 (m, 1H), 6.19 (d, J =16.6 Hz, 1H), 5.75 (d, J = 10.2 Hz, 1H), 4.96-4.74 (m, 1.5H), 4.52-4.44(m, 0.5H), 4.24-4.14 (m, 1.5H), 3.94-3.69 (m, 5H), 3.50- 3.48 (m, 0.5H),2.90-2.70 (m, 1H), 2.19 (s, 3H), 1.46- 1.10 (m, 12H). 169

632.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.46 (s, 1H), 8.17 (s, 1H),7.51-7.45 (m, 1H), 7.42 (d, J = 9.5 Hz, 1H), 7.34-7.18 (m, 3H),6.89-6.77 (m, 1H), 6.19 (dd, J = 16.6, 2.2 Hz, 1H), 5.80-5.71 (m, 1H),4.92-4.83 (m, 1H), 4.79-4.74 (m, 0.5H), 4.50-4.43 (m, 0.5H), 4.23- 4.10(m, 1.5H), 3.96-3.74 (m, 5H), 3.53-3.48 (m, 0.5H), 2.98-2.69 (m, 1H),1.47-1.05 (m, 12H). 170

632.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.45 (s, 1H), 8.17 (s, 1H),7.52-7.44 (m, 1H), 7.41 (d, J = 9.5 Hz, 1H), 7.36-7.14 (m, 3H),6.90-6.77 (m, 1H), 6.19 (d, J = 16.7 Hz, 1H), 5.80-5.71 (m, 1H),4.93-4.83 (m, 1H), 4.81-4.74 (m, 0.5H), 4.53-4.45 (m, 0.5H), 4.25-4.10(m, 1.5H), 3.98-3.60 (m, 5H), 3.52-3.48 (m, 0.5H), 2.91- 2.80 (m, 1H),1.50-1.02 (m, 12H). 171

645.6 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.09 (s, 1H), 8.45 (s, 1H), 8.27(s, 1H), 7.20 (dd, J = 15.5, 8.0 Hz, 1H), 6.93-6.73 (m, 1H), 6.68-6.63(m, 2H), 6.20 (dd, J = 16.6, 2.1 Hz, 1H), 5.83-5.66 (m, 1H), 4.87-4.78(m, 1.5H), 4.52-4.45 (m, 0.5H), 4.18-4.14 (m, 1.5H), 3.91- 3.86 (m, 2H),3.78 (s, 3H), 3.53-3.49 (m, 0.5H), 2.85- 2.70 (m, 1H), 2.18-2.13 (m,3H), 1.36-1.17 (m, 12H). 172

645.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.05 (s, 1H), 8.46 (s, 1H), 8.27(s, 1H), 7.20 (dd, J = 15.5, 8.0 Hz, 1H), 6.89-6.79 (m, 1H), 6.70-6.56(m, 2H), 6.19 (dd, J = 16.6, 2.1 Hz, 1H), 5.80-5.72 (m, 1H), 4.92-4.73(m, 1.5H), 4.53-4.43 (m, 0.5H), 4.24-4.07 (m, 1.5H), 3.96- 3.81 (m, 2H),3.77 (s, 3H), 3.55-3.48 (m, 0.5H), 2.79- 2.65 (m, 1H), 2.14 (s, 3H),1.46-1.10 (m, 12H). 173

647.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.52-8.45 (m, 1H), 8.17 (s, 1H),7.44-7.36 (m, 1H), 7.08-6.98 (m, 1H), 6.90-6.79 (m, 1H), 6.46-6.38 (m,1H), 6.35-6.27 (m, 1H), 6.20 (dd, J = 16.6, 2.1 Hz, 1H), 5.79-5.72 (m,1H), 5.09 (d, J = 14.9 Hz, 2H), 4.90-4.74 (m, 1.5H), 4.53- 4.45 (m,0.5H), 4.18-4.07 (m, 1.5H), 3.98-3.73 (m, 5H), 3.57-3.47 (m, 0.5H),3.06-2.99 (m, 0.5H), 2.94-2.87 (m, 0.5H), 1.45-1.08 (m, 12H). 174

647.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.46-8.37 (m, 1H), 8.17 (s, 1H),7.45-7.36 (m, 1H), 7.08-6.98 (m, 1H), 6.91-6.80 (m, 1H), 6.46-6.36 (m,1H), 6.30 (dd, J = 18.3, 9.5 Hz, 1H), 6.20 (dd, J = 16.6, 2.2 Hz, 1H),5.80- 5.72 (m, 1H), 5.20-5.10 (m, 2H), 4.89-4.75 (m, 1.5H), 4.55-4.46(m, 0.5H), 4.20-4.08 (m, 1.5H), 4.00-3.68 (m, 5H), 3.53-3.45 (m, 0.5H),2.99-2.94 (m, 0.5H), 2.84- 2.78 (m, 0.5H), 1.50-1.05 (m, 12H). 175

644.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.50-8.40 (m, 1H), 8.27 (s, 1H),7.06-6.97 (m, 1H), 6.90-6.78 (m, 1H), 6.41 (d, J = 8.2 Hz, 1H),6.34-6.24 (m, 1H), 6.20 (d, J = 16.4 Hz, 1H), 5.81-5.71 (m, 1H), 5.12(d, J = 16.0 Hz, 2H), 4.92-4.71 (m, 1.5H), 4.53-4.45 (m, 0.5H), 4.17-4.08 (m, 1.5H), 3.98-3.92 (m, 2H), 3.79 (s, 3H), 3.60- 3.47 (m, 0.5H),2.96-2.81 (m, 0.5H), 2.75-2.64 (m, 0.5H), 2.25-2.05 (m, 3H), 1.37-1.13(m, 12H). 176

644.2 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.46 (s, 1H), 8.28 (s, 1H), 7.01(dd, J = 15.1, 8.0 Hz, 1H), 6.92-6.77 (m, 1H), 6.40 (d, J = 8.2 Hz, 1H),6.34-6.24 (m, 1H), 6.20 (d, J = 16.4 Hz, 1H), 5.79-5.70 (m, 1H), 5.11(d, J = 9.0 Hz, 2H), 4.92-4.71 (m, 1.5H), 4.55-4.44 (m, 0.5H), 4.18-4.01(m, 1.5H), 3.99-3.86 (m, 2H), 3.78 (s, 3H), 3.62-3.48 (m, 0.5H),2.94-2.58 (m, 1H), 2.25-2.05 (m, 3H), 1.45-1.10 (m, 12H). 177

645.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.44-8.37 (m, 1H), 8.11-8.09 (m,1H), 7.35-7.30 (m, 1H), 7.04-7.00 (m, 1H), 6.86-6.75 (m, 1H), 6.44-6.40(m, 1H), 6.33- 6.28 (m, 1H), 6.17 (dd, J = 16.8 Hz, 2.4 Hz, 1H), 5.74-5.69 (m, 1H), 5.15 (s, 2H), 4.90-4.40 (m, 2H), 4.20-3.90 (m, 2H),3.89-3.80 (m, 2H), 3.74 (d, J = 8.0 Hz, 3H), 3.55-3.44 (m, 1H),1.65-1.62 (m, 1H), 1.46-1.45 (m, 1H), 1.33-1.11 (m, 7H), 0.76-0.64 (m,2H). FNMR (376 MHz, DMSO-d₆, ppm): δ −114.55 (1F), −126.97 (1F). 178

645.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.44-8.31 (m, 1H), 8.09 (s, 1H),7.33-7.29 (m, 1H), 7.05-6.99 (m, 1H), 6.83-6.75 (m, 1H), 6.44-6.41 (m,1H), 6.33-6.28 (m, 1H), 6.19-6.13 (m, 1H), 5.74-5.70 (m, 1H), 5.20-5.13(m, 2H), 4.83-4.73 (m, 2H), 4.25-4.00 (m, 2H), 3.95- 3.75 (m, 2H),3.75-3.73 (m, 3H), 3.51-3.35 (m, 1H), 1.68-1.61 (m, 2H), 1.44-1.12 (m,7H), 0.77-0.66 (m, 2H). FNMR (376 MHz, DMSO-d₆, ppm): δ −113.89 (1F),−127.94 (1F). 181

629.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.49 (s, 1H), 8.33 (s, 1H),7.54-7.41 (m, 1H), 7.32-7.15 (m, 3H), 6.91-6.74 (m, 1H), 6.19 (dd, J =16.6, 1.9 Hz, 1H), 5.81- 5.71 (m, 1H), 4.96-4.82 (m, 1H), 4.82-4.73 (m,0.5H), 4.56-4.36 (m, 0.5H), 4.24-4.06 (m, 1.5H), 4.00-3.84 (m, 2H), 3.80(s, 3H), 3.57-3.44 (m, 0.5H), 2.83-2.68 (m, 1H), 2.19 (s, 3H), 1.40-1.30(m, 3H), 1.28-1.14 (m, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7Hz, 3H). 182

629.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.49- 8.48 (m, 1H), 8.32 (s, 1H),7.50-7.44 (m, 1H), 7.30-7.18 (m, 3H), 6.90-6.79 (m, 1H), 6.22- 6.17 (m,1H), 5.78-5.74 (m, 1H), 4.87-4.75 (m, 1.5H), 4.56-4.44 (m, 0.5H),4.21-4.14 (m, 1.5H), 3.97-3.78 (m, 5H), 3.53-3.49 (m, 0.5H), 2.78-2.72(m, 1H), 2.16 (s, 3H), 1.36-1.33 (m, 3H), 1.27-1.18 (m, 3H), 1.14-1.02(m, 6H). 183

644.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.51- 8.44 (m, 1H), 8.32 (s, 1H),7.05-6.97 (m, 1H), 6.88-6.78 (m, 1H), 6.43-6.37 (m, 1H), 6.31- 6.24-6.16(m, 2H), 5.79-5.72 (m, 1H), 5.12 (s, 2H), 4.92-4.72 (m, 1.5H), 4.52-4.44(m, 0.5H), 4.47-4.04 (m, 1.5H), 4.03-3.76 (m, 5H), 3.60- 3.53 (m, 0.5H),2.89-2.81 (m, 0.5H), 2.75-2.62 (m, 0.5H), 2.30-2.05 (m, 2H), 2.08 (s,1H), 1.37-1.07 (m, 9H), 1.06-0.90 (m, 3H). 184

644.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.45- 8.43 (m, 1H), 8.32 (s, 1H),7.04-6.99 (m, 1H), 6.91-6.80 (m, 1H), 6.42-6.38 (m, 1H), 6.32- 6.18 (m,2H), 5.78-5.74 (m, 1H), 5.13-5.04 (m, 2H), 4.95-4.75 (m, 1.5H),4.60-4.45 (m, 0.5H), 4.18-4.08 (m, 1.5H), 3.93-3.80 (m, 5H), 3.56- 3.47(m, 0.5H), 2.95-2.85 (m, 0.5H), 2.73-2.60 (m, 0.5H), 2.19-2.02 (m, 3H),1.35-1.20 (m, 6H), 1.14-0.95 (m, 6H). 185

645.3 HNMR (400 MHz, DMSO-d₆, ppm): δ 8.46 (s, 1H), 8.32 (s, 1H),7.25-7.13 (m, 1H), 6.88- 6.76 (m, 1H), 6.70-6.50 (m, 2H), 6.24-6.15 (m,1H), 5.80-5.72 (m, 1H), 4.93-4.72 (m, 1.5H), 4.52-4.43 (m, 0.5H),4.22-4.07 (m, 1.5H), 3.98-3.80 (m, 5H), 3.56-3.48 (m, 0.5H), 2.79- 2.69(m, 1H), 2.23-2.07 (m, 3H), 1.38-1.28 (m, 3H), 1.27-1.03 (m, 6H),1.03-0.89 (m, 3H). 186

645.4 HNMR (400 MHz, DMSO-d₆, ppm): δ 10.05 (s, 1H), 8.44 (s, 1H), 8.31(s, 1H), 7.22-7.17 (m, 1H), 6.90-6.78 (m, 1H), 6.70-6.58 (m, 2H),6.21-6.17 (m, 1H), 5.78-5.74 (m, 1H), 4.93-4.75 (m, 1.5H), 4.55-4.42 (m,0.5H), 4.27-4.08 (m, 1.5H), 3.90-3.74 (m, 5H), 3.51- 3.47 (m, 0.5H),2.80-2.70 (m, 1H), 2.15-2.07 (m, 3H), 1.36-1.32 (m, 3H), 1.31-1.10 (m,6H), 1.04-0.96 (m, 3H).

Biological Example 1. Assay for Cell Proliferation

Lung cancer cell line NCI-H358 (ATCC CRL-5807) containing KRas G12Cmutation was grown in RPMI 1640 medium supplemented with 10% fetalbovine serum, penicillin/streptomycin. One hundred fifty microliter (150μL) of media containing 2000 cells per well were seeded into each wellof a 96-well culture plate and left to attach overnight in a 37° C.incubator with 5% CO2. Diluted compounds of 0.75 μL for each well wereadded by liquid handler at a final concentration of 0.5% DMSO. Cellswere treated for 5 days in the incubator. Cell-titer Glo (CTG) kit(Promega) was used to assess cell proliferation. Of note, 120 μL of CTGreagent was added to each well and incubated at RT for 10 minutes. Theluminescence signal was then collected on Envision 2104 plate reader.

TABLE 2 Inhibition of NCI-H358 Cell Proliferation by RepresentativeCompounds Compound IC₅₀ (nM) Control A* 4.7 1 10.0 2 23.9 3 660.8 4129.8 5 171.6 6 4.9 7 30.6 8 11.2 9 4.1 11 9.2 12 106.6 13 6.5 14 8.8 168.0 17 14.4 18 16.0 19 5.0 20 6.7 21 29.9 22 7.6 23 6.9 24 9.1 25 52.526 167.6 27 69.9 28 23.3 29 11.4 30 52.7 31 28.2 32 8.5 33 67.5 34 58.335 58.2 36 >3000 37 >3000 38 >3000 39 38.2 40 7.5 41 6.9 42 38.5 43 15.544 2.1 45 298.8 46 81.5 47 23.8 48 25.8 49 25.0 50 106.7 51 12.5 52 22.853 617.2 54 34.6 55 74.3 56 27.0 59 >3000 60 81.7 61 71.2 62 15.9 6517.6 66 19.9 67 46.5 68 344.0 69 7.8 70 15.1 71 20.1 72 13.1 73 66.0 745.7 77 8.6 78 10.4 79 12.9 80 8.1 81 35.9 82 10.8 83 5.9 84 6.9 85 9.786 8.6 87 4.1 88 21.2 89 1.5 91 7.8 92 2.8 93 1.8 94 37.5 95 14.6 9610.8 97 7.3 98 7.4 99 5.8 100 14.1 101 25.8 102 37.4 103 47.6 105 8.8106 10.2 107 5.2 108 46.5 109 12.3 110 10.1 111 6.3 112 32.1 113 48.5114 497.3 115 4.6 116 15.8 117 12.9 118 40.2 119 9.6 120 145.9 121 >3000122 >3000 123 >3000 124 2.4 125 6.1 126 0.6 127 3.5 128 8.7 131 210.4132 157.3 140 58.7 141 38.0 142 2.2 143 1300 144 2.5 145 1.4 146 1100147 2.7 148 78.6 149 12.8 150 1.1 151 16.2 152 0.4 153 172.2 154 1.4 15560.0 156 6.9 157 151.9 158 1.8 159 64.2 160 1.3 161 32.4 162 0.5 16344.2 164 >1000 165 157.2 166 1.5 167 0.8 168 20.3 169 118.8 170 1.0 17115.6 172 1.2 173 23.5 174 0.2 175 16.1 176 0.5 177 73.7 178 0.9 179386.5 180 7.8 181 44.4 182 1.7 183 27.4 184 0.2 185 21.7 186 0.9*Control A:(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

The in vitro data above show that changing the R⁸ position (see e.g.,Formula I-IV) from 2-fluorophenyl group to 2-amino-6-fluoro-phenyl groupcan result in almost 20 fold enhancement of potency in some series ofcompounds but not in others. Compound Nos. 126 and 128 are identicalexcept with respect to the R⁸ position, but Compound No. 126 with a2-amino-6-fluoro-phenyl group is about 15× more potent than Compound No.128 with a 2-fluoro-phenyl group, IC₅₀ of 0.6 nM vs. 8.7 nM. Similarly,Compound Nos. 44 and 42 are identical except with respect to the R⁸position, but Compound No. 44 with a 2-amino-6-fluoro-phenyl group isabout 19× more potent than Compound No. 42 with a 2-fluoro-phenyl group,IC₅₀ of 2.1 nM vs. 39.5 nM. However, this does not mean that anycompound with a 2-amino-6-fluoro-phenyl group at the R⁸ position has amuch improved potency over those having a 2-fluoro-phenyl group at theR⁸ position. For example, Compound Nos. 78 and 48 are also are identicalexcept with respect to the R⁸ position, and Compound No. 78 with a2-amino-6-fluoro-phenyl group is only slightly more potent than CompoundNo. 48 with a 2-fluoro-phenyl, IC₅₀ of 10.4 nM vs. 25.8 nM. We have alsotested the IC₅₀s using the same assay (NCI-H358 assay discussed above)for4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneand4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;the compound having a 2-amino-6-fluoro-phenyl group is only slightlymore potent than the compound with a 2-fluoro-phenyl group, IC₅₀ of 1.6nM vs. 4.0 nM. Additionally, the IC₅₀ of4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-onewas tested to be 5.3 nM using the same assay (NCI-H358 assay discussedabove); and the corresponding compound with 2-fluorophenyl group,4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluorophenyl)-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-onewas tested to have an IC₅₀ of 19.0 nM using the same assay. These datashow that compounds with 4,6-dicyclopropylpyrimidin-5-yl group and2-amino-6-fluoro-phenyl at the R⁸ position are better fitted forinhibiting the KRAS G12C enzyme. This is in contrast with data showingthat when changing an isopropyl group into a cyclopropyl group on thepyrimidine ring, a drop in potency of about 2-6 fold is expected,compare for example, Compound Nos. 2 and 5, 49 and 50, etc. This trendis generally observed except for compounds having2-amino-6-fluoro-phenyl at the R⁸ position; in these series ofcompounds, the trend is reversed, with cyclopropyl-pyrimidyl compoundsmore potent than the corresponding isopropylpyrimidyl compounds.

Biological Example 2. Human Hepatocyte Clearance Study

The in vitro human hepatocyte clearance of compounds described here wasstudied using pooled human hepatocytes purchased from BioreclamationIVT(Westbury, N.Y., Cat #X008001, Lot #TQJ). The assay was conductedaccording to manufacturer's instruction. Briefly, 10 mM stock solutionsof test compounds and positive control (Verapamil) were prepared in 100%DMSO. Thawing media (50 mL) used in the study consists of 31 mL WilliamsE medium (GIBCO Cat #12551-032), 15 mL isotonic percoll (GE HealthcareCat #17-0891-09), 500 uL 100× GlutaMax (GIBCO Cat #35050), 750 uL HEPES(GIBCO Cat #15630-080), 2.5 mL FBS (Corning Cat #35-076-CVR), 50 uLhuman insulin (GIBCO Cat #12585-014) and 5 uL dexamethasone (NICPBP).Incubation media is made of Williams E medium supplemented with 1×GlutaMax. Both thawing medium and incubation medium (serum-free) wereplaced in a 37° C. water bath for at least 15 minutes prior to use.Compound stock solutions were diluted to 100 μM by combining 198 μL of50% acetonitrile/50% water and 2 μL of 10 mM stock solution. Verapamilwas use as positive control in the assay. Vials of cryopreservedhepatocytes were removed from storage and thawed in a 37° C. water bathwith gentle shaking. Contents of the vial were poured into the 50 mLthawing medium conical tube. Vials were centrifuged at 100 g for 10minutes at room temperature. Thawing medium was aspirated andhepatocytes were re-suspended with serum-free incubation medium to yield˜1.5×10⁶ cells/mL. Hepatocyte viability and density were counted using aTrypan Blue exclusion, and then cells were diluted with serum-freeincubation medium to a working cell density of 0.5×10⁶ viable cells/mL.Then, a portion of the hepatocytes at 0.5×10⁶ viable cells/mL was boiledfor 5 minutes prior to adding to the plate as negative control toeliminate the enzymatic activity so that little or no substrate turnovershould be observed. The boiled hepatocytes were used to prepare negativesamples. Aliquots of 198 μL hepatocytes were dispensed into each well ofa 96-well non-coated plate. The plate was placed in the incubator on anorbital shaker at 500 rpm for approximately 10 minutes. Aliquots of 2 μLof the 100 μM test compound or positive control were added intorespective wells of the non-coated 96-well plate to start the reaction.This assay was performed in duplicate. The plate was incubated in theincubator on an orbital shaker at 500 rpm for the designated timepoints. Twenty-five microliter of contents were transferred and mixedwith 6 volumes (150 μL) of cold acetonitrile with IS (200 nM imipramine,200 nM labetalol and 200 nM diclofenac) to terminate the reaction attime points of 0, 15, 30, 60, 90 and 120 minutes. Samples werecentrifuged at 3,220 g for 25 minutes and aliquots of 150 μL of thesupernatants were used for LC-MS/MS analysis. For data analysis, allcalculations were carried out using Microsoft Excel. Peak areas weredetermined from extracted ion chromatograms. The in vitro half-life(t_(1/2)) of parent compound was determined by regression analysis ofthe percent parent disappearance vs. time curve. The in vitro half-life(in vitro t_(1/2)) was determined from the slope value: in vitrot_(1/2)=0.693/k. Conversion of the in vitro t_(1/2) (in minutes) intothe scale-up unbound intrinsic clearance (Scaled-up unbound CL_(int), inmL/min/kg) was done using the following equation (mean of duplicatedeterminations): Scaled-up unbound CL_(int)=kV/N×scaling factor, whereV=incubation volume (0.5 mL); N=number of hepatocytes per well (0.25×10⁶cells). Scaling factors for in vivo intrinsic clearance prediction usinghuman hepatocytes are listed as: liver weight (g liver/kg body weight):25.7; hepatocyte concentration (10⁶ cells/g liver): 99; scaling factor:2544.3.

TABLE 3 Human Hepatocyte Clearance of Exemplary Compounds HumanHepatocyte Human In vitro Remaining Percentage @ Human In vitro Cl_(int)Human Scale-up Compound 120 min (%) T_(1/2) (min) (μl/min/10⁶ cells)Cl_(int) (mL/min/kg) Control A^(a) 22.4 57.6 24.1 61.2  1 27.9 66.5 20.853.0  6 33.4 71.7 19.3 49.2  8 2.1 21.7 63.8 162.4  9 18.6 50.2 27.670.2  13 103 ∞^(b) 0.00^(b) 0.00^(b)  14 75.7 306 4.5 11.5  20 74.3 2745.1 12.9  21 90.6 784 1.8 4.5  22 83.3 472 2.9 7.5  23 82.4 554 2.5 6.4 24 70.1 234 5.9 15.1  28 61.1 164 8.4 21.5  29 60.8 163 8.5 21.7 40^(c) 20.7 54.6 12.7 32.3  41^(c) 38.9 84.3 8.2 20.9  44^(c) 61.7 1724.0 10.2  52 65.3 190 7.3 18.5  72 41.2 104 13.3 34.0 124^(c) 37.5 81.28.5 21.7 125^(c) 16.5 48.0 14.5 36.8 126^(c) 47.8 103.9 6.6 17.0 127^(c)55.5 158.3 4.4 11.1 128^(c) 39.9 67.5 10.3 26.1 145^(c) 82.9 688.4 1.02.6 ^(a)Control A:(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one.^(b)If calculated CLint < 0, then T_(1/2) and CLint were reported as “∞”and “0.00”, respectively. ^(c)Working cell density is 2 × 10⁶ viablecells/mL instead of 0.5 × 10⁶ viable cells/mL.

Biological Example 3. Rat PK Studies

The pharmacokinetic (PK) profile of compounds following single i.g in SDrat obtained from SIPPER B&K Laboratory Animal Co., LTD of Shanghai wasdetermined. Three female rats of weight around 220 g were used.Compounds were prepared at 1 mg/ml with the formulation of 10% DMSO+10%solutol HS15+80% (10% HPβCD in water). Blood samples (0.2 mL) werecollected at 0 h (pre-dose) and 0.25, 0.5, 1, 2, 4, 8, 24 h time pointsafter administration of compounds at the dose of 10 mg/kg.

The collected blood samples were centrifuged without delay and theplasma was separated and transferred into tubes before storage at −70°C. prior to analysis. Aliquots of the plasma unknowns, blank andcalibration standards were placed in 1.5 mL tubes and mixed withacetonitrile/methanol (1/1, v/v) containing IS. After vortexing for 5min, each sample was centrifuged at 14000 rpm at 4° C. for 10 min. Thesupernatant were injected into the LC-MS/MS system.

Samples were separated using a Simazhu LC-30D UPLC system equipped witha Shimadzu Shim-pack GIST C18, (2.1*50 mm 2 μm) at 45° C. Eluates wereanalyzed using an API4000 Q-Trap mass spectrometer with a TurboIonSprayinterface. Chromatographic separation was done with a mobile phasecomposed of water with 0.1% formic acid (solution A) and acetonitrilewith 0.1% formic acid (solution B). The mobile phase was delivered at aflow rate of 0.6 mL/min, using a stepwise gradient elution program. Toimprove the sensitivity of the test compound screening, a MRM method inpositive electrospray ionization mode was employed. Mass spectrometrydata was acquired and analyzed using AB Sciex Analyst version 1.6.2software. The pharmacokinetic parameters were derived using standardnoncompartmental methods with Phoenix WinNonLin Professional Version8.1. The following pharmacokinetic parameters were calculated: terminalhalf-life (T½), area under concentration-time curve (AUC), T_(max),C_(max), clearance, apparent distribution volume, mean residence timeand other parameters.

TABLE 4 Rat PK Data of Selected Compounds Rat PO (10 mpk) Rat PO (10mpk) Rat PO (10 mpk) Compound F % C_(max) (uM) AUC last (uM · hr) 44 71%1.38 4.3 Control B^(a) 16% 1.0  3.6 126 54% 1.06 3.8 Control C^(b) 12%1.0  2.3 ^(a)Control B:4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one^(b)Control C:4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.

Biological Example 4. In Vivo Studies to Evaluate KRAS G12C Inhibitorsas a Mono Drug or Combinations with Other Agents

All the procedures related to animal handling, care and the treatment inthis study were performed according to the guidelines approved by theInstitutional Animal Care and Use Committee (IACUC) of SIPPER B&Kfollowing the guidance of the Association for Assessment andAccreditation of Laboratory Animal Care (AAALAC). At the time of routinemonitoring, the animals were checked for any effects of tumor growth onnormal behavior such as mobility, food and water consumption (by lookingonly), body weight gain/loss (body weights were measured twice weekly),eye/hair matting and any other abnormal effect. Death and observedclinical signs were recorded on the basis of the numbers of animalswithin each subset. Animals that were observed to be in a continuingdeteriorating condition were euthanized prior to death or beforereaching a comatose state

The NCI-H358, SW837, NCI-H2122 tumor cells were purchased from theAmerican Type Culture Collection (ATCC). Cells were maintained in vitroas monolayer cultured in RPMI-1640 or DMEM medium supplemented with 10%fetal bovine serum, 50 IU/ml penicillin/streptomycin (GIBCO) at 37° C.in an atmosphere of 5% CO₂ in air. The tumor cells were routinely subcultured twice weekly by trypsin-EDTA treatment. The cells growing in anexponential growth phase were harvested and counted for tumorinoculation.

For tumor bearing models, female 6- to 8-week-old athymic BALB/c nudemice were used for human cancer cell lines. Each mouse was inoculatedsubcutaneously at the right flank with tumor cells (10×10⁶) in 0.1 ml ofPBS. The treatments were started when the average tumor size reachedapproximately 200-250 mm³. Carboplatin, Cisplatin was injected twice aweek by i.p. Vehicles and other test articles were given orally as asuspension by gavage once daily during the study or treatment period.

Tumor volume was calculated by measuring two perpendicular diametersusing the following formula: (L×W 2)/2 in which L and W refer to thelength and width tumor diameter, respectively. Results are expressed asmean and standard deviation of the mean.

The results of various treatments are shown in FIGS. 1-6. FIGS. 1-3compare the efficacy of some representative compounds of the presentdisclosure with AMG510, which is currently in Phase I/II clinical trialfor the treatment of KRAS G12C mutant non-small cell lung cancer,colorectal cancer, and appendix cancer. AMG510 is believed to be6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-1H,2H-pyrido[2,3-d]pyrimidin-2-one.In FIG. 1, it was shown that Compound No. 44 at a dose of 60 mg/kg andCompound No. 126 at a dose of 30 mg/kg are more effective than AMG510 at60 mg/kg in reducing tumor volume in vivo in colorectal adenocarcinomaSW837 xenograft model throughout the treatment period. FIG. 2 shows thatCompound No. 44 at a dose of 30 mg/kg and Compound No. 126 at a dose of30 mg/kg are more effective than AMG510 at 30 mg/kg in reducing tumorvolume in vivo in NSCLC H358 xenograft model. FIG. 3 shows that CompoundNo. 126 at a dose of 60 mg/kg are more effective than AMG510 at 60 mg/kgin reducing tumor volume in vivo in NSCLC H2122 xenograft model.

FIGS. 4-6 show that compounds of the present disclosure can be used incombination with other anticancer therapy to achieve synergistic effectagainst various cancers. FIG. 4 shows that in a NSCLC H358 xenograftmodel, the combined treatment with carboplatin and Compound No. 145shows much better reduction of tumor volume throughout the course oftreatment when compared to treatment with either carboplatin or CompoundNo. 145 alone. In this study, the treatments include: carboplatin at 30mg/kg; Compound 145 at 5 mg/kg; or carboplatin at 30 mg/kg and Compound145 at 5 mg/kg. FIG. 5 shows that in a NSCLC H358 xenograft model, thecombined treatment with cisplatin and Compound No. 126 shows much betterreduction of tumor volume throughout the course of treatment whencompared to treatment with either cisplatin or Compound No. 126 alone.Similarly, the combined treatment with RMC-4550 and Compound No. 126shows much better reduction of tumor volume throughout the course oftreatment when compared to treatment with either RMC-4550 or CompoundNo. 126 alone. In this study, the treatments include: cisplatin at 2mg/kg; RMC-4550 at 10 mg/kg; Compound 126 at 5 mg/kg; cisplatin at 2mg/kg and Compound 126 at 5 mg/kg; or RMC-4550 at 10 mg/kg and Compound126 at 5 mg/kg. FIG. 6 shows that in a colorectal adenocarcinoma SW837xenograft model, the combined treatment with trametinib and Compound No.44 shows much better reduction of tumor volume throughout the course oftreatment when compared to treatment with either trametinib or CompoundNo. 44 alone. In this study, the treatments include: trametinib at 1mg/kg; Compound 44 at 30 mg/kg; or trametinib at 1 mg/kg and Compound 44at 30 mg/kg.

The Summary and Abstract sections may set forth one or more but not allexemplary embodiments of the present invention as contemplated by theinventor(s), and thus, are not intended to limit the present inventionand the appended claims in any way.

The present invention has been described above with the aid offunctional building blocks illustrating the implementation of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have been arbitrarily defined herein for the convenienceof the description. Alternate boundaries can be defined so long as thespecified functions and relationships thereof are appropriatelyperformed.

With respect to aspects of the invention described as a genus, allindividual species are individually considered separate aspects of theinvention. If aspects of the invention are described as “comprising” afeature, embodiments also are contemplated “consisting of” or“consisting essentially of” the feature.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments.

All of the various aspects, embodiments, and options described hereincan be combined in any and all variations.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent that any meaning or definition of a term in this documentconflicts with any meaning or definition of the same term in a documentincorporated by reference, the meaning or definition assigned to thatterm in this document shall govern.

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein: X is O, NR¹⁰, S, SO₂, or an optionally substituted 4 to 7 membered heterocyclic ring; R¹ is hydrogen, optionally substituted C₁₋₄ alkyl, or -L-R²⁰, wherein L is absent or an optionally substituted C₁₋₄ alkylene, optionally substituted C₁₋₄ heteroalkylene, optionally substituted C₃₋₆ carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, wherein R²⁰ is hydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, —NR²¹R²², —OR²³, an optionally substituted 4 to 7 membered heterocyclyl, or X—R¹ represents —COOH, —COOR²³, —CONR²¹R²², —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₃₋₆ cycloalkyl is optionally substituted, e.g., with 1-3 groups each independently selected from F, OH, protected OH, and C₁₋₄ alkoxy; wherein each of R¹⁰, R²¹ and R²² at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; R²³ at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group; each of A¹, A², A³, A⁴, and A⁵ is independently CR³⁰ or N, wherein R³⁰ at each occurrence is independently hydrogen, F, Cl, C₁₋₄ alkyl, or C₁₋₄ alkoxyl; or R¹, X, and A¹ together form an optionally substituted heterocyclic or heteroaryl ring; R² and R³ are each independently hydrogen, halogen, —OH, —CN, optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or optionally substituted C₁₋₄ alkoxy; Het is a 4-10 membered heterocyclic ring, optionally substituted with independently selected R⁴ group(s), (R⁴)_(n), wherein n is 0, 1, 2, or 3, and R⁴ at each occurrence is independently C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), fluorine substituted C₁₋₄ alkyl, hydroxyl substituted C₁₋₄ alkyl, or cyano substituted C₁₋₄ alkyl; or two R⁴ groups can join together to form a 3-6 membered ring structure; U represents an electrophilic moiety capable of forming a covalent bond with a cysteine residue of a KRAS protein, e.g., a KRAS G12C mutant protein; R⁷ is hydrogen, halogen, CN, a 3-4 membered ring, (e.g., cyclopropyl), optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, or optionally substituted C₁₋₄ alkoxyl; and R⁸ is an optionally substituted aryl or optionally substituted heteroaryl.
 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-1 or I-2:

wherein: X is O, S, N, or NR¹⁰, each of J¹ and J² is independently selected from O, S, N, CR⁴⁰, and NR⁴¹, wherein each of R⁴⁰ and R⁴¹ at each occurrence is independently hydrogen, OH, CN, halogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, an optionally substituted C₁₋₄ alkoxy, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, R⁵ and R⁶ are each independently hydrogen, halogen, —CN, —COOR^(23A), —CONR^(21A)R^(22A), optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4 to 7 membered heterocyclic ring, or R⁵ and R⁶ can join together to form an optionally substituted C₃₋₆ carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, wherein each of R^(21A) and R^(22A) at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; and R^(23A) at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group; wherein the dotted line indicates that the respective connection is a single or double bond, provided that the bicyclic ring as a whole is aromatic.
 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C:

wherein A² is CH or N, and each of R¹⁰, R⁴⁰ and R⁴¹ at each occurrence is independently hydrogen or a C₁₋₄ alkyl.
 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-5 or I-6:

wherein: R⁵ and R⁶ are each independently hydrogen, halogen, —CN, —COOR^(23A), —CONR^(21A)R^(22A), optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4 to 7 membered heterocyclic ring, or R⁵ and R⁶ can join together to form an optionally substituted C₃₋₆ carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, wherein each of R^(21A) and R^(22A) at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; and R^(23A) at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group; L is absent, an optionally substituted C₁₋₄ alkylene, or optionally substituted 4 to 7 membered heterocyclic ring containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), wherein R²⁰ is hydrogen, optionally substituted C₁₋₄ alkyl, —NR²¹R²², —OR²³, an optionally substituted 4 to 7 membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), each of R²¹, R²² and R²³ at each occurrence is independently hydrogen or an optionally substituted C₁₋₄ alkyl.
 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the —O-L-R²⁰ residue is:


6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized as having Formula I-7 or I-8:

wherein: R⁵ and R⁶ are each independently hydrogen, halogen, —CN, —COOR^(23A), —CONR^(21A)R^(22A), optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4 to 7 membered heterocyclic ring, or R⁵ and R⁶ can join together to form an optionally substituted C₃₋₆ carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, wherein each of R^(21A) and R^(22A) at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; and R^(23A) at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionally substituted C₁₋₄ heteroalkyl, optionally substituted C₃₋₆ carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group; L is absent, an optionally substituted C₁₋₄ alkylene, or optionally substituted 4 to 7 membered heterocyclic ring containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), wherein R²⁰ is hydrogen, optionally substituted C₁₋₄ alkyl, —NR²¹R²², —OR²³, an optionally substituted 4 to 7 membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), wherein ring B is a 4-7 membered heterocyclic ring containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), optionally substituted with R⁴² group(s), (R⁴²)_(m), wherein R⁴² at each occurrence is independently hydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, —NR²¹R²², or —OR²³, and m is 0, 1, or 2; each of R¹⁰, R²¹ and R²² at each occurrence is independently hydrogen, an optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, or a nitrogen protecting group; and R²³ at each occurrence is independently hydrogen or an optionally substituted C₁₋₄ alkyl.
 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, which has a Formula according to I-7, wherein the

moiety in Formula I-7 is selected from —NH₂, —NHCH₃, —NHC(O)CH₃, —N(CH₃)SO₂CH₃, —N(CH₃)₂, and


8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, which has a Formula according to 1-8, wherein the ring B together with the optional substituent(s) R⁴² is


9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein —X—R¹ is —C(CH₃)₂OH.
 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both A¹ and A² are N.
 11. (canceled)
 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² and R³ are independently selected from hydrogen, C₁₋₄ alkyl optionally substituted with 1-3 fluorine, C₃₋₆ cycloalkyl, and halogen.
 13. (canceled)
 14. (canceled)
 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² and R³ are both isopropyl or both cyclopropyl.
 16. (canceled)
 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Het in Formula I, together with (R⁴)_(n) and U, is represented by

wherein n is 0, 1, or 2, wherein when n is 1 or 2, R⁴ at each occurrence is independently methyl, ethyl, —CF₃, —CF₂H, —CH₂OH, or —CH₂CN.
 18. (canceled)
 19. (canceled)
 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A³ is N, A⁴ is CH, and A⁵ is N.
 21. (canceled)
 22. (canceled)
 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is hydrogen, F, Cl, methyl, or CF₃.
 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁸ is a phenyl optionally substituted with 1-3 groups each independently selected from F, Cl, —OH, NH₂, protected hydroxyl group, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy.
 25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁸ is a bicyclic heteroaryl optionally substituted with 1-3 groups each independently selected from F, Cl, —OH, NH₂, protected hydroxyl group, protected amino group, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, 3 or 4 membered ring, C₁₋₄ alkoxy, fluorine substituted C₁₋₄ alkyl, and fluorine substituted C₁₋₄ alkoxy.
 26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from:

27.-42. (canceled)
 43. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
 44. A method of inhibiting KRAS G12C mutant protein in a cell, the method comprising contacting the cell with the compound of claim 1 or a pharmaceutically acceptable salt thereof.
 45. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
 46. The method of claim 45, wherein the cancer is a hematologic malignancy, lung cancer, pancreatic cancer, endometrial cancer, gall bladder cancer, thyroid cancer, bile duct cancer, and/or colorectal cancer.
 47. The method of claim 45, further comprising treating the subject with an additional therapy.
 48. The method of claim 47, wherein the additional therapy is a chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy.
 49. The method of claim 45, wherein the subject has a G12C mutation of KRAS, HRAS and/or NRAS. 